Evaluation of a Novel PET Radioligand as an Inflammatory Biomarker in Musculoskeletal Conditions
Phase: PHASE1
Conditions: Myositis, Inflammatory, Rheumatoid Arthritis, Healthy Volunteers
Sponsor: National Institute of Mental Health (NIMH)

 
  
Abbreviated Title:  PET in MSK Conditions 
NIH IRB #:  19M0079 
Version Date:  04/16/2024 
 
 
 
 
 
Title: Evaluation of a Novel PET Radioligand as an Inflammatory Biomarker in Musculoskeletal 
Conditions 
 
 
 
 
 
 
 
NIH Principal Investigator:   
Robert B. Innis, M.D., Ph.D. A, B, C, D, E, F 
National Institute of Mental Health/MIB 
10 Center Drive 
Building 10, Room B1D43J  
Telephone: 301-594-1368 
Fax:  301-480-3610 
Email:  robert.innis@nih.gov  
 
 
 
 
 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 2 of 40 
 
Total requested accrual     
 
 (42) Patients with rheumatoid arthritis 
 (15) Patients with myositis  
 (15) Patients with axial spondyloarthritis  
 (39) Healthy Volunteers  
 
  
 
Project Uses Ionizing Radiation:  
 No   
 Yes  
  
 
Medically-indicated only 
  
 
Research-related only  
  
 
Both  
 
IND/IDE 
 
 
 
 No   
Yes  
 
 
Drug/Device/#_142872 for [11C]MC1_____ 
 
 
Sponsor: __NIMH IRP______ 
 
Durable Power of Attorney   
 No   
 Yes  
 
Multi-institutional Project 
 
No   
 Yes  
 
 
 
 
 
Institution#1___University of Maryland School of Medicine _FWA #___0007145______  
Date of IRB approval ___07/28/2022__________________  
 
 
Institution#2_________________    FWA #_________  
Date of IRB approval ______________  
 
Data and Safety Monitoring Board   No   
 Yes  
 
Technology Transfer Agreement  
 No   
 Yes  
 
Samples are being stored  
 
 No   
 Yes  
 
Covered Protocol Requiring DEC Clearance (per SOP 21)  No   
 Yes 
 
Approved for Short Form Consent Process for Non-English Speakers  No 
  Yes 
 
Flesch-Kincaid reading level of consent form:  
• Healthy volunteer for Phase 1 study: 8.5  
• Healthy volunteer for Phase 2 study: 8.7  
• RA patient for Phase 2 study: 8.7 
• IIM patient for Phase 2 study: 8.7 
• AxSpA patient for Phase 2 study: 8.7 
• Healthy volunteer for Phase 3:  8.7 
• RA patient for Phase 3:  8.7 
• RA patient for Phase 4:  8.7   
 
 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 3 of 40 
PRÉCIS: 
I. 
Objective 
Cyclooxygenase-2 (COX-2) is implicated in the pathophysiology of various inflammatory 
disorders, suggesting that both may serve as potential biomarkers of inflammation in brain as 
well as periphery. Our laboratory recently developed [11C]MC1 to image COX-2. Using whole-
body imaging, this study seeks to determine whether PET imaging using this new radioligand 
can differentiate three inflammatory conditions—rheumatoid arthritis (RA), axial 
spondyloarthritis (AxSpA) and idiopathic inflammatory myopathies (IIM)—from healthy 
conditions. To determine if [11C]MC1 uptake is specific to COX-2, we will also conduct a 
blocking study with a selective COX-2 inhibitor (celecoxib). Using brain-dedicated imaging, this 
seeks to determine whether RA patients and healthy volunteers have specific binding in brain – 
i.e., uptake that can be blocked celecoxib.  
 
II. 
Study population 
Healthy volunteers (n = 17), patients with RA (n = 15), and patients with IIM (n = 15) will 
undergo whole-body PET/CT scans. Patients with AxSpA (n=15) will undergo two whole-body 
PET/MRI scans. In addition, healthy volunteers (n = 22) and patients with RA (n = 12) will have 
brain-dedicated imaging using [11C]MC1 concurrent with arterial blood sampling. Finally, 15 
patients with RA will be imaged during a period of moderate to severe symptoms and after 
clinically indicated treatment for two to four months. Thus, the entire population will be healthy 
volunteers (n = 39), patients with RA (n = 42), patients with AxSpA (n=15) and patients with 
IIM (n = 15). 
 
III. 
Design 
a) 
Phase 1: We will begin by injecting up to 10 mCi of [11C]MC1 in one healthy male and 
one healthy female and then conducting a whole-body PET scan. Uptake will be measured in the 
ovaries and testes, and the dose of radioactivity will be calculated. We will proceed only if the 
dose to these organs with the higher injected activity proposed for Phase 2 will not exceed the 
limits specified by the Radioactive Drug Research Committee (RDRC). 
 
b) 
Phase 2: 15 RA patients, 15 IIM patients and 15 age-, sex-, and genotype-matched 
healthy subjects will undergo two whole-body PET/CT scans using 15 mCi of [11C]MC1. 15 
AxSpA patients will  undergo two whole-body PET/MRI scans using 15 mCi of [11C]MC1. The 
first scan will serve as the baseline scan for comparison; the second scan will be a blocking study 
using celecoxib. 
 
c) 
Phase 3: 12 RA patients and 22 age- and sex-matched healthy subjects will undergo two 
brain-dedicated PET/CT scans, each using 20 mCi [11C]MC1, and concurrent with arterial blood 
sampling. The first scan will be a baseline scan, and the second will be after blockade by 
celecoxib. 
 
d) 
Phase 4: 15 RA participants will be imaged twice with [11C]MC1: while having moderate 
to severe symptoms and after clinically-indicated therapy for about two to four months. 
Participants will have whole-body scan after injection of 15 mCi of [11C]MC1. 
 
IV. 
Outcome measures 
For whole body imaging, radioligand uptake in a selected region of interest will be 
quantified as a Standardized Uptake Value (SUV), which normalizes for injected activity and 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 4 of 40 
body weight. Possible differences in actual blood radioligand level may be adjusted by venous 
blood data obtained during the PET scan. Regional uptake after blockade with celecoxib will be 
expressed as a percentage of the baseline value. The baseline uptake and the percentage blockade 
by celecoxib of each radioligand will be compared between patients and healthy subjects as well 
as between inflamed and non-inflamed regions of the body in RA, AxSpA, and IIM patients. 
For brain-dedicated imaging, the density of COX-2 will be measured with 
pharmacokinetic modeling and expressed as distribution volume (VT). 
 
 

Abbreviated Title: PET in MSK Conditions 
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TABLE OF CONTENTS  
 
PRÉCIS:..................................................................................................................................................................... 3 
LIST OF ABBREVIATIONS ............................................................................................................................... 6 
1. INTRODUCTION AND BACKGROUND ................................................................................................... 6 
2. STUDY OBJECTIVES ....................................................................................................................................14 
3. SUBJECTS..........................................................................................................................................................15 
4. STUDY DESIGN AND METHODS .............................................................................................................17 
5. MANAGEMENT OF DATA AND SAMPLES ..........................................................................................22 
6. ADDITIONAL CONSIDERATIONS ..........................................................................................................23 
7. RISKS AND DISCOMFORTS ......................................................................................................................24 
8. SUBJECT SAFETY MONITORING...........................................................................................................27 
9. OUTCOME MEASURES ...............................................................................................................................27 
10. STATISTICAL ANALYSIS .........................................................................................................................28 
11. HUMAN SUBJECTS PROTECTION .......................................................................................................28 
13. CONSENT DOCUMENTS AND PROCESS ...........................................................................................29 
14. DATA AND SAFETY MONITORING .....................................................................................................30 
15. QUALITY ASSURANCE (QA) ...................................................................................................................30 
16. REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND PROTOCOL 
DEVIATIONS ........................................................................................................................................................31 
17. ALTERNATIVES TO PARTICIPATION ...............................................................................................32 
18. PRIVACY .........................................................................................................................................................32 
19. CONFIDENTIALITY ....................................................................................................................................32 
20. CONFLICT OF INTEREST ........................................................................................................................33 
21. RESEARCH AND TRAVEL COMPENSATION ..................................................................................33 
22. REFERENCES ................................................................................................................................................37 
 
 
 

Abbreviated Title: PET in MSK Conditions 
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page 6 of 40 
 
LIST OF ABBREVIATIONS 
TSPO  
18-kDa translocator protein 
PET 
 
positron emission tomography 
FDG  
fluorodeoxyglucose 
MDD  
major depressive disorder 
LAB  
low-affinity binder 
HAB  
high-affinity binder 
MAB  
mixed-affinity binder 
COX  
cyclooxygenase 
IC50 
 
half maximal inhibitory concentration 
HPLC  
high-performance liquid chromatography 
NSAID 
non-steroidal anti-inflammatory drug 
LPS 
 
lipopolysaccharide 
MRI 
 
magnetic resonance imaging 
SUV  
standardized uptake value 
VT  
 
total (specific plus nondisplaceable) distribution volume 
RA 
 
rheumatoid arthritis 
AxSpA 
axial spondyloarthritis 
AS 
 
ankylosing spondylitis 
IIM 
 
idiopathic inflammatory myopathies 
PM 
 
polymyositis 
DM 
 
dermatomyositis 
IMNM  
immune-mediated necrotizing myopathy 
IBM 
 
inclusion body myositis 
1.  
INTRODUCTION AND BACKGROUND 
 
Inflammation plays a significant role in various disorders that involve neurodegeneration 
or autoimmune reaction as one of their mechanisms. Although positron emission tomography 
(PET) imaging is capable of visualizing, characterizing, and measuring inflammatory processes 
at the molecular level, most PET radioligands that target inflammatory mediators have not made 
the successful transition from preclinical to human study due to the low sensitivity or non-
specific bindings of the radioligands themselves or to other issues such as species differences. 
Although it is not a specific biomarker of inflammation, [18F]FDG remains the most widely used 
PET radioligand in inflammation studies in humans. With regard to inflammation-specific PET 
imaging biomarkers, 18-kDa translocator protein (TSPO) radioligands have been the most 
successful in human studies.  
 
 
COX-2 as a new target for inflammatory biomarkers 
Just as neuroinflammation may play a pathophysiological role in neuropsychiatric 
disorders, anti-inflammatory drugs may be therapeutically useful. For this reason, we have 
developed PET radioligands for cyclooxygenase (COX), a well-known target of non-steroidal 
anti-inflammatory drugs (NSAIDs). COX is the rate-limiting enzyme in the synthesis of 
prostaglandins from arachidonic acid and exists as two primary isoforms—COX-1 and COX-2 
(Fig. 3). NSAIDs such as aspirin and ibuprofen inhibit the function of both COX-1 and COX-2 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 7 of 40 
non-selectively or selectively. Inhibition of the COX system by NSAIDs attenuates both central 
and peripheral inflammation.  
 
 
Figure 3. The two primary COX enzymes, COX-1 and COX-2, regulate the rate-limiting steps in the metabolic 
pathway of arachidonic acid and in the production of pro-inflammatory agents such as prostaglandins and 
thromboxanes. 
 
The COX-1 radioligand, [11C]PS13, is the first direct-acting radioligand and is now being 
tested in healthy subjects (Protocol 17-M-0179). While COX-1 is constitutively expressed, 
COX-2 is known to be inducible, contributing to increased production of pro-inflammatory 
agents in pathologic conditions. Accordingly, COX-2 has been an important target for 
developing anti-inflammatory treatment to prevent or decelerate the progression of 
neuropsychiatric and autoimmune disorders. For instance, celecoxib and naproxen have been 
used in a clinical prevention trial in Alzheimer’s disease, but had no significant effect on clinical 
outcome (The Alzheimer's Disease Anti-inflammatory Prevention Trial Research, 2013). 
However, because no reliable COX-2 biomarker exists, interpreting negative results in this and 
other studies has been limited; specifically, it remains unclear whether the agents’ ability to 
inhibit COX activity was insufficient or whether COX inhibition itself did not significantly affect 
disease progression. Thus, developing a COX-2 PET radioligand as an inflammatory biomarker 
is necessary to further evaluate and monitor the effects of anti-inflammatory treatments.  
 
Development of a PET radioligand selective for COX-2 
Substituted pyrimidines, such as 6-methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-
2-ylmethyl)pyrimidin-4-amine (MC1), display many desirable properties for development as 
PET radioligands. A set of five substituted pyrimidines, including MC1, was synthesized by 
modifying published procedures (Orjales et al., 2008). When these ligands were tested for 
affinity to COX-2 and COX-1 in human blood, they showed high affinities for COX-2 in the nM 
range. Because MC1 had one of the highest affinities (IC50 = 3 nM) and selectivities (> 1000-
fold) over binding to COX-2, it was selected for labeling with carbon-11 by treating the 
desmethyl-precursor 1 and base in DMF with [11C]MeI. [11C]MC1 was separated by HPLC and 
formulated for intravenous injection.  
 
We performed [11C]MC1 whole-body PET/CT in rhesus monkeys. As shown in Figure 4, 
there was no specific binding of [11C]MC1 in any organs in healthy monkeys. Although a few 
organs have been shown to constitutively express COX-2 under normal conditions, COX-2 is 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 8 of 40 
predominantly induced with inflammation. Thus, we developed an inflammation model in 
monkey with lipopolysaccharide (LPS) injection into the brain. LPS was injected into the right 
putamen of two monkeys to induce transient neuroinflammation, and brain PET scans were 
obtained on post-injection Days 1, 3, and 8. To measure specific uptake, blocked scans were also 
performed with non-radioactive MC1 (0.3 mg/kg). The specific uptake of [11C]MC1 was not 
observed in brain under baseline conditions, and brain uptake was increased after LPS injection 
on Day 1; the percentage of increased uptake was ~60% (Fig. 5). This upregulation was 
confirmed postmortem with measurements of COX-2 protein and its cognate mRNA (Shrestha et 
al. J. Neuroimmunology, submitted). 
 
 
 
 
 
Figure 4. Uptake of radioactivity in a rhesus monkey after injection of [11C]MC1 under baseline conditions (left) 
and 10 minutes after injection of nonradioactive MC1 (0.3 mg/kg i.v.) (right). High uptake was only observed in 
excretory organs such as the biliary system, the liver, and the urinary bladder at baseline. Uptake was not blocked in 
any of these areas by pharmacological dose of MC1.  
 
 

Abbreviated Title: PET in MSK Conditions 
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Figure 5. Brain uptake of radioactivity 
in a rhesus monkey one day after 
injection of lipopolysaccharide (LPS) 
into the right putamen. To obtain 
specific binding of [11C]MC1 to COX-2, 
non-radioactive MC1 (0.3 mg/kg i.v.) was 
injected 10 minutes before the second 
scan. Non-radioactive MC1 blocked 
radioligand binding to COX-2 and 
decreased brain uptake compared to the 
baseline condition. The PET images are 
shown as standardized uptake value 
(SUV), which adjusts for injected activity 
and body weight. MRI images show the 
anatomical structures for the co-registered 
PET images 
 
. 
 
To examine whether a second LPS injection would cause an even larger increase of 
COX-2, two animals were injected with LPS a second time (Shrestha et al., J. 
Neuroinflammation, submitted). The second injection caused a marked increase of COX-2 at the 
injection site, which could be blocked by nonradioactive MC1 (Fig. 6) – i.e., the uptake was 
specifically bound to COX-2. 
 
 
 
Figure 6. Parametric distribution 
volume (VT) images of [11C]MC1 
uptake on Day 1 after the second 
lipopolysaccharide (LPS) injection in a 
monkey. Upper row: [11C]MC1 uptake 
was markedly increased surrounding the 
injection area in the right putamen. 
Bottom row: MC1 blocked radioligand 
binding to COX-2 at the injection site 
(marked by red arrow) to a level lower 
than that in the remainder of the brain. 

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page 10 of 40 
 
Our interpretation was that [11C]MC1 lacked the sensitivity to measure the low basal 
concentrations of COX-2, but could detect the enzyme after upregulation, which can be a 10- to 
20-fold effect. We wondered if postmortem measurements of the density of COX-2 in monkey 
and human brain could guide the feasibility of detecting COX-2 in humans, either healthy 
volunteers or patients with neuroinflammation. Unfortunately, such postmortem measurements 
are not possible because COX-2 is rapidly upregulated and metabolized, with a degradation half-
life of only a few hours (Learn et al., 2000; Kang et al., 2007). We confirmed this finding by 
measuring COX-2 via ELISA in monkey brain that was rapidly harvested after death (i.e., within 
15 min) and postmortem human brain (typical with a postmortem interval of one to two days). 
The concentration of COX-2 in human brain was 10-100 fold lower than that in rapidly 
harvested monkey brain. Thus, a study of COX-2 in human diseases cannot be performed with 
postmortem tissue. Instead, it will require PET to measure in vivo concentrations of this dynamic 
biomarker of inflammation. 
To determine whether [11C]MC1 can detect COX-2 in any human condition, we studied 
patients with rheumatoid arthritis (RA), as COX-2 is upregulated in the affected joints.  
 
Preliminary Results in RA Patients 
To date, we have studied three RA patients. The first two patients had moderately 
symptomatic joints in the hands, arms, and/or shoulders. Those symptomatic joints had increased 
uptake of [11C]MC1, which was partially blocked by celecoxib, a COX-2 selective inhibitor (Fig. 
7). The third RA patient had joints that were relatively mildly affected at the time of the PET 
scan and showed no increased uptake of [11C]MC1. 
 
Figure 7. Human positron emission 
tomography (PET) images of 
cyclooxygenase-2 (COX-2) in Patient 1 with 
rheumatoid arthritis and a healthy control. 
Increased [11C]MC1 uptake in the bilateral hand 
joints reflected increased COX-2 binding in 
Patient 1 compared to the healthy control. The 
increased [11C]MC1 uptake in Patient 1 with 
rheumatoid arthritis was partially blocked by 
celecoxib (400 mg) – i.e., the uptake was not 
reduced to that in control subjects. We seek to 
determine whether a higher dose (600 mg) will 
cause a greater blockade.  
 
As described above, we found no specific binding of [11C]MC1 to COX-2 in the brain of 
healthy monkeys, where specific uptake means it can be blocked by celecoxib. For this reason, 
we intracerebrally injected lipopolysaccharide (LPS) to induce COX-2 expression to determine 
whether the radioligand works in vivo. When we started in human subjects, we also expected to 
find no specific binding in brain. To our surprise, the first two RA patients and two healthy 

Abbreviated Title: PET in MSK Conditions 
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page 11 of 40 
volunteers had brain uptake that was blocked by celecoxib: about 30% in RA and 20% in 
controls (Fig. 8). However, these results from only PET imaging (i.e., time-activity curves) can 
be misleading, as celecoxib could have had a peripheral rather than a central effect. For example, 
celecoxib might have increased the peripheral clearance of [11C]MC1. To determine whether 
celecoxib’s effect is central (i.e., blocking the enzyme) rather than peripheral (e.g., increased 
clearance), we need to measure the amount of radioligand delivered arterially to brain. That is, 
pharmacokinetic modeling with arterial blood measurements can separate central from peripheral 
effects. 
We doubt celecoxib’s effect was peripheral for two reasons. First, if it increased 
clearance, then all organs should have less uptake. However, most organs, including lung, liver, 
thyroid, kidney, and GI tract, were unaffected by celecoxib. Second, the effect on clearance 
would have had to be specific for [11C]MC1, as celecoxib was unable to block uptake of 
[11C]ER176 (which binds to TSPO) in affected joints of RA patients. 
 
0
50
100
0
1
2
3
4
5
Baseline
Blocked by Celecoxib
26% blocking by AUC
Time (min)
Conc radioactivity (SUV)
0
50
100
0
2
4
6
Baseline
Blocked by Celecoxib
32% blocking by AUC
Time (min)
Conc radioactivity (SUV)
0
50
100
0
1
2
3
4
5
Baseline
Blocked by Celecoxib
20% blocking by AUC
Time (min)
Conc radioactivity (SUV)
0
50
100
0
1
2
3
4
Baseline
Blocked by Celecoxib
21% blocking by AUC
Time (min)
Conc radioactivity (SUV)
Patient
Control
# 1
# 2
 
 
Figure 8. Brain uptake of [11C]MC1 at baseline and after blockade by celecoxib (400 mg) in 
two patients with rheumatoid arthritis and two healthy controls. These time-activity curves 
suggest celecoxib is blocking radioligand binding to COX-2 in brain, by ~20% in controls and 
~30% in patients. An alternative interpretation is that celecoxib acted peripherally to decrease the 
amount radioligand delivered to the brain. To address this question, we propose quantitative brain 
imaging with arterial blood sampling to measure and then to correct for any peripheral effect of 
celecoxib. A third RA patient was recently analysed and had only 9% blockade by area-under-the-
curve (AUC). 
 
 
 
 

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page 12 of 40 
 
Necessity of a human study in peripheral inflammatory condition 
The COX-2 radioligand, [11C]MC1, is the first successful radioligand for this target. 
COX-2 is more typically expressed in peripheral organs than in brain. Indeed, most selective 
COX-2 inhibitors were primarily developed to treat peripheral inflammatory disorders such as 
arthritis and chronic musculoskeletal pain, and limited data exist on their penetration to brain. As 
noted above, COX-2 is rarely detected in non-inflammatory conditions, suggesting that any new 
radioligand should be tested in inflammatory conditions with more robust expression of COX-2. 
For example, MDD would not be appropriate to evaluate this radioligand, as a negative result 
could reflect either that the radioligand does not work in vivo or that MDD does not have 
elevated COX-2. Although results from the LPS-injected monkey study (Fig. 5) suggested 
significant specific binding of [11C]MC1 to COX-2, which was induced by neuroinflammation, 
low signal-to-noise ratio in the image was still a limitation; high non-specific binding in the 
background was due to the high lipophilicity of [11C]MC1 and to the high lipid content of the 
entire brain. To resolve this, [11C]MC1 would need to be tested in peripheral inflammation with 
lower background lipid content. We observed [11C]MC1 uptake in the ovaries of a female 
monkey that was blocked by both nonradioactive MC1 and celecoxib (a selective COX-2 
inhibitor). This is in line with the notion that the ovary highly expresses COX-2 even under 
normal conditions as long as it is actively involved in the ovulation cycle (McCann et al., 2013). 
Even if the ovaries showed relatively higher specific uptake of [11C]MC1 than other organs in 
monkey study, our dosimetry calculation confirmed that actual radiation exposure to the ovaries 
is not higher than those with other 11C radioligands. The radiation exposure in the ovaries is 
compared in Table 1 assuming that 15 mCi of each radioligand is injected. Most of these 11C 
radioligands have been widely used in human studies. 
 
Table 1. Comparison of radiation exposure to ovaries with 15 mCi of 11C radioligands 
Radioligand 
[11C]MC1 
[11C]PK11195 
[11C]CUMI 
[11C]PIB 
[11C]DPA-
713 
Radiation exposure 
to ovaries (rem) 
0.21 
0.18 
0.21 
0.18 
0.22 
 
However, ovaries are not an appropriate organ for testing our new radioligand because of 
their small size and significant movement during the scans. Thus, from the perspective of 
radioligand development, this first-in-human study of [11C]MC1 would be most useful if 
conducted in patients with representative peripheral inflammatory disorders: rheumatoid arthritis 
(RA) and idiopathic inflammatory myopathies (IIM).  
If [11C]MC1 effectively images COX-2 in RA, AxSpA, and in IIM, it will be used in two 
general ways relevant to neuropsychiatric disorders, to investigate pathophysiology and to guide 
therapeutic trials with NSAIDs. Having validated [11C]MC1 in human disorders known to have 
elevated COX-2, it could be used to determine whether AD and MDD also show such an 
elevation. With regard to treatment, it is largely unknown the extent to which various NSAIDs 
enter brain and their relative in vivo selectivity for COX-1 versus COX-2. Validated radioligands 
for both COX-1 and COX-2 would help address these questions. In the brain, however, the 
relative roles of these two isozymes are controversial. Increasing evidence suggests that COX-1 
is more pathologic than COX-2 (Choi et al., 2009). Furthermore, the selective COX-2 inhibitor, 
rofecoxib, had detrimental effects on cognition in a relatively large study of AD patients (Aisen 
et al., 2008). In summary, both COX-1 and COX-2 may have important pathophysiological roles 

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page 13 of 40 
in neuropsychiatric disorders. Radioligands selected for each isoform would be useful both to 
explore pathophysiological and potentially to guide therapeutic trials of NSAIDs. 
 
Figure 6. Uptake of radioactivity in ovaries of a female rhesus monkey after injection of [11C]MC1 at baseline (top), 
10 minutes after injection of nonradioactive MC1 (0.3 mg/kg i.v.) (middle), and CT images showing the 
corresponding anatomical structures (bottom). High uptake was observed in both ovaries and was blocked by a 
pharmacological dose of MC1, consistent with specific binding to COX-2. The PET images are shown as 
standardized uptake value (SUV), which adjusts for injected activity and body weight. 
 
 
Rheumatoid arthritis (RA) 
RA is estimated to affect between one and four percent of the United States population, 
causing significant losses in work and social functioning as well as increases in health-related 
costs and disability across the general population, including in the minority community. Early 
diagnosis and monitoring of disease activity is important for proper treatment and good 
prognosis, lending increased urgency to the importance of developing an inflammatory 
biomarker for RA.  
RA is an inflammatory autoimmune disease of the joints and involves migration of 
macrophages and T helper lymphocytes into inflamed areas (Tak et al., 1997; Steiner et al., 
1999). An [18F]FDG PET imaging study found that inflamed joints could be differentiated from 
normal non-inflamed joints (Elzinga et al., 2007). However, because glucose metabolism can be 
increased for a number of reasons, more specific markers of inflammation are needed to be 
clinically useful.  
  
NSAIDs target COX-1 and 2 and are often recommended as first-line therapy in RA. To 
prevent the common gastrointestinal side effect of NSAIDs, which mostly result from COX-1 
inhibition, selective COX-2 inhibitors have been developed to treat RA. One of these is 
celecoxib, which showed significant anti-inflammatory and analgesic activity in RA patients in 

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page 14 of 40 
large clinical trials (Emery et al., 1999; Tsuji et al., 2012). Increased expression of COX-2, but 
not COX-1, has also been demonstrated in rheumatoid synovial tissues (Crofford et al., 1994). 
Thus, COX-2 is considered to be a key mediator in the inflammatory processes that underlie the 
development of clinical symptoms in RA.  
 
Idiopathic inflammatory myopathies (IIM) 
The IIM are characterized by the presence of inflammation in skeletal muscle. The 
clinical course of IIMs can vary widely ranging from a slowly progressive weakness over years 
with no extraskeletal muscle involvement to rapidly disabling weakness with severe interstitial 
lung fibrosis within a matter of weeks to months. Approximately five to 10 new cases per million 
per year occur in the United States and the disorders are somewhat more common in females 
than males. Bohan and Peter classified IIM patients into two major categories: polymyositis 
(PM) and dermatomyositis (DM) (Bohan and Peter, 1975a, b). In PM and DM, lymphocytes, 
dendritic cells, and macrophages infiltrate the inflamed muscle. Among the IIMs, immune-
mediated necrotizing myopathy (IMNM) is considered to be a predominantly macrophage-
mediated immune response. Inclusion body myositis (IBM) is another type of IIM, which shows 
distinctive clinical presentation and pathologic findings. Any of these conditions could be 
associated with the high expression of COX-2.  
PET studies in IIM have been almost exclusively limited to [18F]FDG PET, and muscle 
biopsy remains the diagnostic gold standard despite the invasiveness of the procedure.  COX-1 
and COX-2 were also shown to be increased in muscle tissues from IIM patients, and 
immunosuppressive treatment led to significant downregulation of COX-2 (Studynkova et al., 
2004; Korotkova et al., 2008). 
 
Axial spondyloarthritis (AxSpA) 
Spondyloarthritis encompasses several immune-mediated inflammatory diseases that 
exhibit overlapping features but differ from other types of inflammatory arthritis in genetic 
predisposition, pathogenesis, and outcome. Axial spondyloarthritis (AxSpA), the most common 
form of SpA includes ankylosing spondylitis (AS), which is the prototypic form of disease. 
AxSpA frequently begins with back pain and stiffness often leads to aberrant ossification and 
ankylosis (fusion) of the spine (AS). Enthesitis, or inflammation where tendons and ligaments 
connect to bones, is the primary pathologic lesion in AxSpA. Our ability to recognize AxSpA 
(early form of AS) involving the axial skeleton, and our understanding of the cause and 
progression of this disease, is limited. 
PET studies in AS have been almost exclusively limited to the evaluation of bone metabolism 
with bone-seeking agents. However, both COX-2 and COX-1 (encoded by PTGS2 and PTGS1, 
respectively) are implicated in AS. PTGS1 variants are associated with progression of AS 
(PMID: 24651623) while PTGS2 variants are associated with disease risk (PMID: 33565113). In 
addition, COX-2 may be overexpressed in vivo in patients with AS, and COX1/2 inhibitors are 
routinely used to treat patients with AS. 
2.  
STUDY OBJECTIVES  
a. Primary objectives 
• To evaluate the PET radioligand [11C]MC1 as a new inflammatory biomarker in 
representative disorders with active inflammation: RA, AxSpA and IIM, compared to 
healthy condition. 

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• To evaluate the specific binding of [11C]MC1 to COX-2 at the inflammatory focus in 
patients versus the same body part in healthy subjects through blocking study using a 
selective COX-2 inhibitor. 
• To measure the brain uptake of [11C]MC1 in brain of RA patients, in comparison to 
healthy volunteers. 
• To evaluate the change of [11C]MC1 binding to COX-2 at the inflammatory focus in 
RA patients: while having moderate to severe symptoms and after two to four months 
of clinically indicated treatment. 
 
b. Secondary objectives 
• To collect the human biodistribution and dosimetry data of [11C]MC1.  
• To see if the uptake of [11C]MC1 at the inflammatory focus is correlated with the 
patient’s available clinical profiles: clinical severity, serum biomarkers, X-ray or MRI 
findings, synovial/muscle biopsy findings, etc.  
• To see if the uptake of [11C]MC1 at the inflammatory focus is correlated with the 
patient’s clinical rating scales and laboratory tests. 
3.  
SUBJECTS 
a.  Description of study populations  
We propose to study four groups of participants: 
1) 17 healthy subjects (2 subjects in Phase 1, and 15 subjects in Phase 2, who are 
age-, sex-, and genotype-matched with patient groups) as well as 22 healthy 
subjects who are age- and sex-matched with the RA patients in Phase 3. 
2) 15 patients with RA (in Phase 2) and 12 patients in Phase 3. 
3) 15 patients with IIM (in Phase 2) 
4) 15 patients with AxSpA (in Phase 2) 
5) 15 patients with RA (in Phase 4) 
Note: As described below in Section 10 (“Statistical Analysis”), these requested 
numbers account for and include subjects who may drop out. 
NIH employees are eligible to participate, but NIH employees who are 
subordinates/relatives/co-workers of investigators will be excluded. NIMH employee 
participation is guided by intramural institute policy.   
 
b.  Inclusion criteria 
1)  Healthy subjects 
• Aged18 years or older. 
• Willing and able to complete all study procedures. 
• Able to provide informed consent. 
• Healthy based on medical history, physical examination, and laboratory testing. 
• Enrolled in protocol #01M0254 “The Evaluation of Participants with Mood and 
Anxiety Disorders and Healthy Volunteers” or #17M0181“Recruitment and 
Characterization of Healthy Research Volunteers for NIMH Intramural Studies”. 
• Be age-, and sex-matched with patient groups for the 15 subjects in the Phase 2. 
 
2)  RA patients 
• Aged 18 years or older. 

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• Willing and able to complete all study procedures. 
• Able to provide informed consent.  
• Have been given a diagnosis of RA based on the published criteria (Aletaha et al., 
2010). 
• Have moderate to severe symptoms, as defined by a DAS28-ESR score >3.2, but 
RA patients may be in remission for the repeat scan in phase 4. 
 
3)  IIM patients 
• Aged 18 years or older. 
• Willing and able to complete all study procedures. 
• Able to provide informed consent.  
• Meets Bohan and Peter criteria (Bohan and Peter, 1975a, b) for probable or 
definite DM or PM, or  
• Meets criteria for IBM as defined by Lloyd et al. (Lloyd et al., 2014): 1) finger 
flexor or quadriceps weakness, and 2) endomysial inflammation, and 3) either 
invasion of non-necrotic muscle fibers or rimmed vacuoles.  
 
4)  AxSpA patients 
• Aged 18 years or older. 
• Willing and able to complete all study procedures. 
• Able to provide informed consent.  
• Have been given a diagnosis of AxSpA based on Assessment of Spondylo-
Arthritis International Society (ASAS) criteria AxSpA (Appendix 1). 
 
c.  Exclusion criteria 
1)  Common for all participants 
• Because non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2, subjects 
should not have taken NSAIDs or willow bark tea for two weeks prior to the PET 
scan.  
• For Phase 2, 3 and 4, *contraindications to taking COX-2 inhibitors that, in the 
opinion of the investigators, have the potential to affect the results or the safety of 
the participant.   
 
These may include:  
o History of hypersensitivity reaction to COX inhibitors or History of aspirin- or 
NSAID-induced asthma;  
o History of upper or lower gastrointestinal bleeding, gastritis, peptic ulcer 
disease; 
o History of uncontrolled gastroesophageal reflux disease (GERD), but not 
medically controlled GERD;  
o Coagulation disorder; 
o Thrombocytopenia;  
o G6PD deficiency;  
o History of gout;  
o History of hepatic or renal impairment;  
o History of cardiovascular disease or presence of cardiovascular risk factors 
such as uncontrolled or poorly controlled hypertension; 

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o Current use of probenecid; 
o Patients clinically in remission or who have low disease activity. 
• HIV Infection. 
• Any other history of severe medical illness or injury with the potential to affect 
study data interpretation or to be any medical contraindication to the procedures 
performed in the study, including active infection and untreated malignancy. 
• Unable to travel to NIH. 
• Recent exposure to radiation related to research (e.g., PET from other research) 
that, when combined with this study, would be above the allowable limits. 
• Inability to lie flat on camera bed for at least two hours, including claustrophobia 
and overweight greater than the maximum for the scanner (500 lb). 
• Pregnancy or breastfeeding.  
• Participants must not have substance use disorder or alcohol use disorder. 
However, alcohol or cannabis use by themselves are not exclusion criteria, unless 
that use affects the function of daily life. 
• NIMH employees or an NIH employee who is a subordinate/relative/co-worker of 
the investigators. 
 
*These criteria will not be applied to the two healthy volunteers participating in the 
Phase 1 of this study. 
 
2)  Healthy subjects 
• Clinically significant laboratory abnormalities based on tests performed under 
screening protocol 01M0254 or 17M0181 and specified in Section 4.c 
“Screening.” 
 
3) AxSpA and IIM patients 
• Unable to have an MRI scan (e.g., pacemakers or other implanted electrical 
devices, brain stimulators, dental implants, aneurysm clips (metal clips on the 
wall of a large artery), metallic prostheses (including metal pins and rods, heart 
valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or 
shrapnel fragments, metal fragments in the eye). 
4.  
STUDY DESIGN AND METHODS 
a. Study overview  
Although most of our prior targets were primarily, if not exclusively, expressed in brain, 
COX-1 and COX-2 are present in the entire body and play important roles in the periphery: 
physiology, pathophysiology, and drug treatment. In fact, our prior studies in monkeys 
demonstrated that COX-1 is expressed at much higher densities in some peripheral organs (e.g., 
spleen, GI tract, and kidney) than in brain. For this reason, the phases of evaluating this COX-2 
radioligand differ from those for brain-dedicated radioligands. That is, we normally do dedicated 
brain kinetic imaging before whole body imaging. For this target, by whole-body imaging in 
patients with RA and IIM, we wish to determine whether the radioligand actually labels COX-2 
(based on blocking studies using a selective COX-2 inhibitor), and whether the most robust 
signal for COX-2 is in the peripheral inflammatory focus by whole-body imaging.  

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This is a multi-site center study in three groups of participants: patients with RA, patients 
with IIM, patients with AxSpA, and healthy volunteers as a control group. As noted above, 
participants must meet inclusion and exclusion criteria and sign an informed consent document. 
This study consists of four phases: 1) initial [11C]MC1 whole-body imaging of two single healthy 
volunteers with a low injection activity; 2) [11C]MC1 whole-body imaging in baseline and pre-
blocked condition with a COX-2 selective antagonist (celecoxib). 3) Dedicated brain imaging 
using [11C]MC1, concurrent arterial blood sampling, in RA patients compared to healthy 
volunteers. 4) [11C]MC1 whole-body imaging of RA patients at baseline and after clinically 
indicated therapy. 
To estimate the radiation exposure from the new radioligand [11C]MC1, we will follow 
the prior suggestions from our laboratory (Zanotti-Fregonara and Innis, 2012), which have been 
approved by the NIH Radiation Safety Committee. Specifically, we found that the average 
exposure of all published human studies with 11C-radioligands more accurately reflected the 
exposure to humans than estimation based on imaging in monkeys with that particular 
radioligand. 
 
Phase 1: We will do whole-body scanning in one male and one female healthy volunteer 
with [11C]MC1 using up to 10 mCi. We will measure uptake in the ovaries and testes and 
calculate the dose of radioactivity. Phase 2 will be proceeded only if the dose to these 
organs from the higher injected activity proposed in Phase 2 will not exceed the limits 
specified by the Radioactive Drug Research Committee (RDRC). If the dose of 
radioactivity already exceeds the RDRC limitation in the first participant of Phase 1, IRB 
will be consulted before the second participant of Phase 2 undergoes [11C]MC1 PET 
scan. 
 
Phase 2: Fifteen patients with RA, fifteen patients with IIM, and fifteen healthy 
volunteers will have two whole-body PET/CT scans using 15 mCi of [11C]MC1. Fifteen 
patients with AxSpA will undergo two whole-body PET/MRI scans using 15 mCi of 
[11C]MC1. The first scan will serve as the baseline for comparison to pre-blocked scan 
and will provide dosimetry information, and the second scan will be a pre-blocking study 
using the COX-2 selective antagonist celecoxib. Two scans are necessary because the 
specific binding can only be estimated by comparing a scan at baseline and a scan after 
blockade. 
 
Phase 3: Twelve RA patients and twenty-two healthy volunteers will have dedicated 
brain imaging with 20 mCi of [11C]MC1 at baseline and after blockade by celecoxib. 
 
Phase 4: Fifteen RA patients will have a whole-body scan with 15 mCi of [11C]MC1 at 
baseline and after two to four months of clinically indicated therapy. The repeat scan will 
be initiated if the RA participant has substantial improvement of symptoms or by four 
months, whichever occurs first. 
 
NOTE: A subject may participate in only one phase of the study. 
 
We will proceed in the order of Phase 1 and 2. In Phase 2, all three groups of participants 
will be recruited and scanned randomly without specific order. Each PET scan will take up to 
two hours. Two PET scans on a day will be separated by at least 2.5 hours to allow for decay of 
the first injection (T1/2 = 20 min). In IIM patients, for the purpose of localizing inflammatory 

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focus in muscle, a whole-body MRI will be obtained before or after the PET scan and can be 
performed on the same day depending on the schedule of the radiology and PET departments. 
The completion of MRI will take approximately one hour. For AxSpA patients, a whole body 
PET/MRI will be obtained meaning that MRI imaging will be done simultaneously with the PET 
scan. MRI is not obtained in RA patients since the inflamed joints are generally well-identified 
by other clinical parameters.  
 
Number of visits and time commitment of participants 
Phase 1: whole-body imaging with 10 mCi [11C]MC1 injection 
1st outpatient visit: pregnancy test; whole body PET (4 hours) 
 
Phase 2: whole-body imaging with 15 mCi [11C]MC1 at baseline and after celecoxib 
1st outpatient visit (only for patients with RA, AxSpA or IIM): clinical evaluations and 
screening procedures; 
2nd outpatient visit (all participants): pregnancy test; baseline & blocked whole body 
PET/CT imaging (8 hours). For AxSpA patients, this will be PET/MRI (8 hours) instead 
of PET/CT. 
3rd or 4th outpatient visit (only for patients with IIM): pregnancy test; whole-body MRI (2 
hours) 
 
Phase 3: brain-dedicated imaging with 20 mCi [11C]MC1 at baseline and after celecoxib 
1st outpatient visit: clinical evaluations and screening procedures 
2nd or 3rd outpatient visit: pregnancy test; baseline & blocked [11C]MC1 PET imaging (8 
hours) 
2nd or 3rd outpatient visit: pregnancy test; brain MRI (2 hours) 
 
Phase 4: whole-body imaging with 15 mCi [11C]MC1 at baseline and after two to four 
months of therapy 
1st outpatient visit (only for patients with RA): clinical evaluations and screening 
procedures 
2nd outpatient visit: pregnancy test; baseline whole body PET imaging (4 hours) 
3rd outpatient visit: pregnancy test; post-therapy whole body PET imaging (4 hours) 
 
All procedures and their associated exposure to radiation are for research purposes only. 
Each subject will not participate in more than one phase of this study. 
 
b. Recruitment 
Patients with RA, AxSpA or IIM will be recruited by advertisements [IRB-approval for 
which will be obtained based on the requirements in OHSRP Policy 302 (“Subject Recruitment 
and Compensation”) placed in medical journals, on websites/email list-servers of medical 
professionals, in patient support group or registry mailings, and/or in a variety of patient support 
group literature and websites, including new patient communication sites, such as Facebook, 
MySpace, Twitter, and Google Adwords for distribution as allowed by NIH policies as needed to 
reach the target enrollment numbers.  AxSpA patients may also be referred from NIAMS 
protocol 11AR0223 (Studies on the Natural History and Pathogenesis of Spondylarthritis). 
    
Healthy volunteers will be recruited under protocol 01M0254 “The Evaluation of 
Participants with Mood and Anxiety Disorders and Healthy Volunteers” or 17M0181, 

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“Recruitment and Characterization of Healthy Research Volunteers for NIMH Intramural 
Studies”.  
Flyers (with tear offs) may be posted on NIH bulletin boards, at coffee shops, grocery 
stores, community centers, bookstores, NIH Clinical Center, libraries or placed in doctor’s office 
waiting rooms, retail establishments as well as on public transportation vehicles and/or bus 
shelters/train stations may be used (all with permission and according to the guidelines of the 
facility) or sent electronically (without tear offs) to those who request a copy. 
Recruitment for Healthy volunteers will also include use of Research Match, Listservs, 
Craig’s List, advocacy websites, resource listings or other website postings and Study-specific 
page on the NIMH-IRP: Join A Study Website with URL (placeholder).  Short text descriptions 
of this study will also appear on Facebook. Facebook posts will be made only via official NIMH 
accounts.  Associate Investigators and members of the NIMH Marketing & Community 
Relations Unit will distribute recruitment materials. 
All recruitment materials, including listserv notices, social media, letters to physicians, 
recruitment website content, and other venues will be approved by the IRB prior to use. 
NIH Employees/staff will not be directly recruited by or through their supervisors or co-
workers to participate in this study. 
 
c. Screening 
Patients with RA, AxSpA or IIM will be screened under this protocol. The screening 
process for AxSpA and IIM patients will additionally ensure that there are no contraindications 
to MRI. Basic screening may include physical exam, medical history, questionnaires, and 
laboratory tests: hematology (CBC with differential); chemistry (electrolytes, LFT’s, glucose, 
BUN, creatinine, Ca, Mg, phosphorus, uric acid, transaminases, total protein, albumin, CK, 
LDH, alkaline phosphatase); urinalysis; urine pregnancy test (females); acute phase reactants 
(ESR, CRP); serology (RF, ANA, immunoglobulins, anti-cardiolipin (ACA), anti-dsDNA, 
ANCA); anti-CCP antibodies and, if clinically indicated, spot urine protein to creatinine ratio. In 
addition, myositis associated or myositis specific antibodies will be obtained, if clinically 
indicated. HIV screening test; hepatitis panel (A, B, C); Tb test; others as required. X-ray, CT or 
MRI of clinically involved area will be obtained if clinically indicated. Additional studies on 
selected subjects, when indicated for diagnosis, will include: muscle biopsy or synovial biopsies 
with a separate informed consent; electromyography (EMG); swallowing tests; and others. 
Screening results will be reviewed by a clinically credentialed investigator before the subject 
undergoes any specific study procedures. No subjects will be withdrawn from NSAIDs including 
aspirin or corticosteroids exclusively for the purpose of participation in this protocol. 
If the RA, AxSpA or IIM subject has had prior NIH laboratory and clinical examinations 
as part protocol #’s 01AR0227 Natural History of Rheumatic Disease in Minority Communities, 
00AR0222 Natural History of Arthritis and Related Conditions, and 11AR0223 Studies on the 
Natural History and Pathogenesis of Spondylarthritis, those results may be used to better 
understand the subject’s current condition. Finally, results within the past year from these three 
natural history protocols can be used as part of screening, rather than repeat these tests under this 
protocol. 
For Phase 4 patients, in addition to a basic rheumatology exam, we will do a Health 
Assessment Questionnaire Disability Index (HAQ-DI for rheumatoid arthritis) and the Disease 
Activity Score in 28 joints (DASB28). The DAS28 is a disease activity score (Prevoo et al., 
1995). These assessments will be done before both scans of Phase 4. 
Healthy volunteers will be screened under protocol 01M0254 or 17M0181. Basic 
screening may include physical exam, medical history, and laboratory tests: CBC; acute care 

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panel; urine pregnancy test (females); HIV screening test; and EKG. Screening results will be 
reviewed by a clinically credentialed investigator before the subject undergoes any specific study 
procedures.  
Consent will be obtained before any study procedures, including screening procedures 
done under this protocol.  
 
d. Study procedures 
 
 
 
1) PET Procedures 
i. 
Radioligands 
[11C]MC1 will be prepared according to the IND and administered via an 
indwelling intravenous catheter over approximately one to three minutes. 
 
ii. 
Insertion of the intravenous and/or arterial line 
Two intravenous lines may be placed in the arms. They are used for the injection 
of radioligand and for drawing venous blood to measure the plasma radioactivity level in 
each time point during the scan. The lines are removed at the end of the day. For Phase 3, 
an arterial catheter will be inserted in the radial artery. 
 
iii. 
PET scan 
For whole-body scans (Phase 2 and 4), PET imaging will be performed using 
PET/CT scanner for about two hours for RA, IIM patients and healthy volunteers. 
AxSpA patients will undergo imaging using PET/MRI scanner for about two 
hours. Participants will be placed on the scanner bed, and to minimize extraneous 
motion, they may wear a head-holding mask and have their arms and abdomen 
wrapped with body-restraining sheets. Almost all subjects find this restraint 
comforting (i.e., they are not afraid of falling off the table), and none have found 
it intolerable. Pre-injection CT transmission scan (for PET) will be performed to 
measure and correct for attenuation. After an intravenous bolus of up to 15 mCi, 
several venous blood samples may be drawn from the venous catheter at discrete 
time points during the PET scan. The total amount of sampling volume will be up 
to 50 mL in each scan. PET image will be acquired in three-dimensional mode 
with increased length of frame for a total of approximately two hours. After the 
scan, the venous line will be removed, and the subject will be instructed to void 
frequently to minimize radiation exposure. 
 
For brain-dedicated scans (Phase 3), the PET procedures will be the same as that 
for whole-body, with two exceptions. 1) Only the head will be scanned and 2) The 
subject’s head may be secured with a thermoplastic mask to prevent excessive 
motion, but it can be removed if the subject finds it uncomfortable. 
 
Pregnancy tests:  For women able to become pregnant, urine pregnancy testing 
will be done within the 24 hours prior to any MRI or PET scan. PET and MRI will not be 
done if the pregnancy test is positive. 
 
iv. 
Administration of celecoxib 
In these whole-body scans, specific binding of [11C]MC1 to COX-2 in the 
inflamed focuses will be verified by pre-blocking study using celecoxib. We will also 

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obtain plasma samples just before and after the PET scan to measure the concentration of 
celecoxib. The dose of celecoxib will not be higher than 600 mg, which is the highest 
single dose for clinical therapeutic purpose. For comparison, the typical adult dose of 
celecoxib is 200 – 400 mg per day. The dose may be adjusted to achieve 40 - 80% 
enzyme occupancy in order to avoid possible side effects, but not to exceed the highest 
dose of 400 mg. 
Participants will be encouraged to have a light meal prior to PET studies with 
blockade by celecoxib. After oral administration, the plasma concentration peaks at about 
two to three hours (Paulson et al., 2001). Thus, we will administer celecoxib about two to 
three hours before the second PET scan. Participants will be monitored by study 
clinicians after drug administration to assess drug associated adverse events. 
 
2) Whole-body MRI 
A whole-body MRI will be obtained for localization of the inflamed muscle in 
patients with IIM and AxSpA will be performed on a scanner located at the NIH Clinical 
Center (Bethesda, Maryland) and will take about one hour. Subjects will undergo safety 
screening prior to the MRI to rule out contraindications such as cardiac pacemaker. 
Pregnancy tests:  For women able to become pregnant, urine pregnancy testing 
will be done within the 24 hours prior to any MRI or PET scan.  PET and MRI will not 
be done if the pregnancy test is positive. 
 
3) Brain MRI 
Subjects in Phase 3 will receive a T-1 weighted MRI of the head within six months of the 
PET scan. A previously acquired MRI scan can be substituted for one on this protocol, if 
acquired within six months of the PET scan. 
 
e. End of participation 
Results of clinical testing from the screening process, diagnostic impression, and MRI 
findings may be shared with patients or referring physicians through the CRIS portal.  
 Such practice is typical for participants undergoing PET studies at the NIMH, since these 
scans are performed for research only, and not routine medical care. Eligible subjects may be 
offered enrollment in other protocols at the NIH. No treatment will be offered.  
Subjects will return to the referring health care provider for treatment and long-term 
management. Subjects who do not have an appropriate health care provider will be referred to 
one in the community.  
5.  
MANAGEMENT OF DATA AND SAMPLES 
a. Storage 
We will follow NIH guidelines to prevent identification of study participants and other 
violations of subject confidentiality. Information will be stored using a confidential case number, 
and no identifiers (name, address, phone number, etc.) will be used that could allow direct 
linking of database information to individual subjects. Secure e-mail will be used for all 
electronic communications of subject information between investigators. Blood samples will be 
discarded at the end of the study. Demographic and clinical data will be archived on a password-
protected server. 
All data will be stored on the NIMH server under password-protected accounts accessible 
only to the principal investigator and directly involved study personnel to preserve subject 

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privacy. All data are regularly backed up, either by the NIMH system administrator or by NIMH 
CIT personnel. 
 
b. Data and sample sharing plan 
No samples will be saved or shared. However, data may be shared with collaborating 
laboratories at the NIH or outside of the NIH and/or submitted to NIH-designated repositories 
and databases if consent for sharing was obtained. Repositories receiving data from this protocol 
may be open-access or restricted access. 
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked from 
an identifying code (“anonymized”). When coded data are shared, the key to the code will not be 
provided to collaborators but will remain at the NIH. Data may be shared with investigators and 
institutions with an FWA or operating under the Declaration of Helsinki (DoH) and reported at 
the time of continuing review. Sharing with investigators without an FWA or not operating under 
the DoH will be submitted for prospective IRB approval. Submission to NIH-sponsored or 
supported databases and repositories will be reported at the time of the Continuing Review. 
Submission to non-NIH sponsored or supported databases and repositories will be submitted for 
prospective IRB approval. 
Required approvals from the collaborating institution will be obtained and materials will 
be shipped in accordance with NIH and federal regulations.    
c. Collaborative Agreement 
This is a multi-site study with NIH as the lead site. The other site is the University of 
Maryland School of Medicine. 
This protocol is a collaboration with investigators at the University of Maryland School 
of Medicine, and it will be performed under a Reliance Agreement in which NIH is the 
responsible IRB.  Investigators at the University of Maryland School of Medicine will recruit 
and screen volunteers with rheumatoid arthritis and myositis and give NIMH’s contact 
information for potential PET study.  They may also ask the volunteers if their contact 
information may be shared with NIMH investigators to contact them directly. If the volunteer is 
interested in participating, we’ll ask him/her to sign the University of Maryland School of 
Medicine’s release of medical information for both clinical and research data to be sent to 
NIMH. If the volunteer is eligible based on this information, the volunteer will be asked to visit 
NIMH to review and sign the consent form. That is, only NIMH investigators will obtain 
consent. After the consent is obtained, we will order any additional data for inclusion and 
exclusion criteria as specified in this protocol. Investigators at NIMH and the University of 
Maryland School of Medicine will bilaterally share clinical and research data that may include 
PII. 
6.  
ADDITIONAL CONSIDERATIONS 
a. Research with investigational drugs or devices 
[11C]MC1 will be prepared under IND 142872. The PET radioligand will be synthesized 
in recently re-established NIMH cGMP facility.  
 
b. Gene therapy 
Not applicable. 

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7. RISKS AND DISCOMFORTS 
Risks include those associated with: a) medical examinations and screening procedures, 
b) MRI, c) placement of a venous line, d) blood sampling, e) radiation exposure from [11C]MC1, 
and the transmission scan, f) PET scanning, and g) celecoxib administration.  
 
a.  Medical examination and screening procedures 
Medical examination and screening procedures are associated with minimal risks that are 
mostly related with phlebotomy for laboratory tests in all participants, and with invasive 
procedures in selected patients such as EMG, muscle biopsy, and synovial biopsy. Phlebotomy 
can be associated with discomfort or bruising. Invasive procedures in selected patients will be 
performed only when clinically indicated under screening protocols with separate informed 
consents. In the present protocol, all subjects are expected to undergo recruitment and 
assessment procedures without any difficulties.  
 
b.  MRI 
MRI scans will be obtained from IIM patients in Phase 2 and in all participants in Phase 3 
as well as for AxSpA patients undergoing PET/MRI scans. People are at risk for injury from the 
MRI magnet if they have pacemakers or other implanted electrical devices, brain stimulators, 
some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic 
prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent 
eyeliner, implanted delivery pump, or shrapnel fragments. Welders and metal workers are also at 
risk for injury because of possible small metal fragments in the eye of which they may be 
unaware. Subjects will be screened for these conditions before having any scan, and if they have 
any, they will not receive an MRI scan.  People with fear of confined spaces may become 
anxious during an MRI. Those with back problems may have back pain or discomfort from lying 
in the scanner. The noise from the scanner is loud enough to damage hearing, especially in 
people who already have hearing loss. Everyone having a research MRI scan will be fitted with 
hearing protection. Subjects will be asked to complete an MRI screening form for each MRI scan 
they have. There are no known long-term risks associated with MRI scans. 
 
c. PET/MRI Scans 
PET/MRI scans involve the risks associated with MRI as stated above. Specifically, the 
risks of MRI include exposure to strong magnetic fields, which may be unsafe for individuals 
with certain implants or devices, and the potential for claustrophobia or discomfort due to the 
enclosed space of the scanner. 
 
The PET/MRI combines MRI with PET imaging, which involves the use of a radioactive 
tracer. However, the radiation exposure from a PET/MRI is lower compared to a PET/CT scan, 
as it does not involve a CT scan. The risks associated with the PET scan include exposure to a 
small amount of radiation, which is generally considered to be within safe limits for diagnostic 
procedures. 
 
d.  Placement of venous and/or arterial lines 
Venous catheter insertion can be associated with discomfort, bruising, infection, or clot 
formation. Using proper placement techniques will minimize these risks. In case of tracer 
extravasation, we will stop the study, remove the venous line from the arm, and apply cold to the 
site. 

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Arterial catheterization has been shown to be a generally safe and reliable method of 
obtaining arterial blood samples (Lockwood, 1985). Placement of a radial arterial catheter may 
cause bruising or infection. There is also a risk of occlusion and microemboli. Over 3,000 arterial 
catheters have been placed to date in the PET Department. Of these, only two complications 
requiring physician’s care arose. In the first case, a small radial artery aneurysm developed 
several months later, which was successfully repaired surgically. In the second case, a radial 
artery thrombosis developed 28 days later, which was also successfully repaired surgically.  
 
e.  Blood sampling 
Participants may have venous blood sampling during PET scans. The total amount of 
blood drawn under this protocol, or the screening protocols will not exceed 400 mL in each 
subject. Blood sampling may lead to the formation of small subcutaneous hematomas caused by 
blood leaking from a punctured blood vessel. Such hematomas cause only minor discomfort. 
They are not dangerous and require no treatment other than reassuring the patient. There is also a 
small risk of infection at the site of the needle puncture, which can be readily treated with 
antibiotic therapy. We will ask participants not to donate blood within 8 weeks prior to the study 
or for 8 weeks following the study.  
 
f.  Radiation exposure risks 
Radiation exposure in this protocol will be from [11C]MC1 and the associated 
transmission scans.  
A whole-body acquisition has been performed in a male and a female volunteer to 
estimate dosimetry. The estimates show an effective dose of 4.6 µSv/MBq (0.017 rem/mCi) and 
that the liver is the target organ, with an equivalent dose of 18 µSv/MBq (0.067 rem/mCi). These 
values are well below the regulatory limits and similar to those of other 11C tracers. Thus, the 
radiation exposure from a single injection of 15 mCi yields an effective dose of 0.26 rem, not 
including the transmission scan (described below). 
With regard to exposure from the transmission scan, the PET Department recently 
implemented Dr. Innis’s suggestion to decrease the current (amperage) and, thereby, the 
radiation from the CT. We do not need a high resolution (high current) image for attenuation 
correction; a low resolution, like that from a line source, is perfectly adequate to correct 
attenuation in the PET emission scan. With the lowered current, the exposure to the lens of the 
eye is now 0.26 rem, about 1/3 of the previous value. 
The effective dose for each whole-body transmission scan from a PET/CT is 0.56 rem. 
We routinely include the dose from additional transmission scan in the event that it must be 
repeated in a subject, so the effective dose for three transmission scans during each day with two 
PET scans (3 * 0.56) is ~1.68 rem. Thus, the total effective dose in two [11C]MC1 PET scans 
(1.68 + 2 * 0.26 rem) is ~2.2 rem. Therefore, the total effective dose in this study is ~2.2 rem, 
which is less than the NIH limit of 5 rem.  
In Phase 3 study, the effective dose for each brain transmission scan from a PET/CT is 
0.02 rem. The effective dose for four transmission scans in the event that it must be repeated in a 
subject during each day with two PET scans (4 * 0.02) is ~0.08 rem. We plan to inject 20 mCi of 
[11C]MC1 in each brain scan which yields an effective dose of 0.34. Thus, the total effective 
dose in two [11C]MC1 scans on each day (0.08 + 2 * 0.34 rem) is ~0.76 rem, which is far less 
than the NIH limit of 5 rem. This dose is described in the consent form as “about 1 rem”.  
In Phase 4 study, the total effective dose in two [11C]MC1 PET scans (1.68 + 2 * 0.26 
rem) is 2.7 rem, which is described in the consent form as “about two rem.” 

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All subjects will be asked about any prior research participation involving radiation 
exposure so that the total exposure, in combination with the present study, will not exceed an 
effective dose of 5 rem per year. 
 
g.  PET scan 
PET scans, which detect injected radioactivity within the body, are not associated with 
any known physical hazards to the subject lying on the table. We routinely use a series of 
procedures to minimize the risk of discomfort during scanning sessions. Namely, the procedures 
are conducted in the presence of trained health professionals to whom participants will have 
ready access should they experience any problems. Participants can communicate with the 
trained health professionals while in the scanner and can be removed from the scanner and 
withdraw from the study at any time if they wish to do so. Participants can also request that the 
operator stop the scan. 
 
h.  Celecoxib administration 
Participants in Phases 2 and 3 will receive a single dose of celecoxib up to 600 mg on 
either day one (Phase 3) or day two (Phase 2). This dose is beyond the normal therapeutic range 
(100- 200 mg BID), but we feel it is safe based on prior experience and celecoxib will be 
administered only short-term – i.e., one or two doses.  
 
 
Prior Experience. 
a) Although the typical dose of celecoxib is 100-200 mg BID, the Food and Drug 
Administration (FDA)-approved package insert (page 1) allows 400 mg BID for 
familial adenomatous polyposis.  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020998s050lbl.pdf 
b) 
Doses up to 2,400 mg/day for up to 10 days in 12 patients did not result in serious 
toxicity (FDA-approved package insert, page 9).   
c) 
Large clinical trials have used celecoxib at doses of 400 mg twice per day for 6 
months. For example, Silverstein and colleagues (Silverstein et al., 2000) studied 
8,059 RA patients taking either celecoxib (400 mg twice per day) or ibuprofen or 
diclofenac, had three arms, with the celecoxib arm patients taking 400 mg twice per 
day for 6 months (Silverstein et al., 2000). This study found a decrease in GI toxicity 
among patients using celecoxib as compared to NSAIDs but they did not note any 
increase in cardiovascular events among these patients (Silverstein et al., 2000). 
d) 
Our collaborator, James Katz, MD, has used up to 600 mg as a single dose in RA 
patients and had no untoward effects. 
 
Short-Term Use. A few studies have examined whether increased cardiac risk is 
associated with short-term use.  In two randomized, double-blind studies patients were 
administered 200 mg of celecoxib daily for 6 weeks without significant increase in 
cardiovascular adverse events (McKenna et al., 2001; Geba et al., 2002). In fact, one 
study demonstrated a superior safety and tolerability profile for celecoxib as compared to 
diclofenac (McKenna et al., 2001). Furthermore, a trial of 7 day treatment of 200 mg 
celecoxib twice daily actually improved outcomes in myocardial injury in elective 
percutaneous intervention for stable angina (Pelliccia et al., 2006). To more thoroughly 
investigate this, a retrospective analysis was conducted of the Veterans Integrated Service 
Network 17 Veterans Affairs database. This identified that patient with long-term 

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celecoxib use was associated with increased cardiovascular risk, but short term use did 
not carry this risk (Motsko et al., 2006).  
 
Common reactions to celecoxib administration include: headache, dyspepsia, urinary 
tract infection, diarrhea, abdominal pain, nausea, vomiting, rash, flatulence, peripheral edema, 
dizziness, AST/ALT elevation, elevated blood urea nitrogen, and photosensitivity. Celecoxib 
carries a Black Box warning for cardiovascular and gastrointestinal risks and that the drug might 
rarely lead to death. Rare but serious reactions associated with celecoxib administration include: 
gastrointestinal bleeding, perforation, or ulcer; myocardial infarction; stroke; thromboembolism; 
hypertension; congestive heart failure; renal papillary necrosis; nephrotoxicity; hepatotoxicity; 
anaphylaxis; bronchospasm; exfoliative dermatitis; Stevens-Johnson syndrome; toxic epidermal 
necrolysis; erythema multiform; anemia; and blood dyscrasias 
(https://online.epocrates.com/rxmain  accessed 3/10/2016). We feel that the risks of serious 
reactions are low as we are giving a single dose of celecoxib within the recommended dose 
range. Subjects will be monitored for adverse reactions. Rarely, a subject will have an allergic 
reaction to their very first dose. Because there is possible teratogenic or nonteratogenic effect of 
celecoxib on pregnancy, participants with child-bearing potential will be required to use 
contraception from the time they are enrolled until three days after the last administration of 
celecoxib. Urine pregnancy testing will be also done before each administration of celecoxib.  
8.  
SUBJECT SAFETY MONITORING 
The subjects will be evaluated upon entry into the protocol. If there are any medical 
contraindications to performing a procedure, that procedure will not be performed. No safety 
labs or EKG will be performed on the day of the PET scan. If the patient has metal in their body 
preventing the safe administration of the MRI, that test will not be performed.   
 
a. Toxicity criteria 
Toxicity will be assessed according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v.4.03   http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
 
b. Criteria for individual subject withdrawal 
Patients will be removed from the study if they become pregnant, are unable to continue 
to cooperate, or have an alteration in clinical status needing medical intervention. Patients may 
withdraw from the trial at any time at their own request. The investigators may withdraw a 
subject for safety or behavioral reasons. 
9.  
OUTCOME MEASURES 
a. Primary outcome measures 
• Phase 2: Difference of [11C]MC1 binding between patients and healthy subjects, 
and between inflamed and uninflamed body parts in RA patients. 
• Phase 2: The specificity of [11C]MC1 binding to COX-2 evaluated by celecoxib-
blocking study. 
• Phase 3: Quantitative measure of enzyme density (VT) at baseline and after 
celecoxib blockade in patients compared to healthy controls. 
• Phase 4: The change of [11C]MC1 binding to COX-2 after two to four months of 
clinically-indicated therapy. 

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b. Secondary outcome measures 
• Biodistribution and dosimetry of [11C]MC1. 
• Clinical correlation of [11C]MC1 inRA, AxSpA and IIM patients based on their 
clinical or laboratory parameters. 
10.  
STATISTICAL ANALYSIS 
a. 
Analysis of data/ study outcomes 
Phase 2 and 4: SUV will be calculated in region-of-interests based on involved body parts 
in patients (e. g. knee joints in RA, thigh muscles in IIM), spine in AxSpA)  using PMOD 
software (PMOD Technologies Ltd., Zurich, Switzerland). Whole-body CT and/or MRI will 
provide guidance for anatomical location of the radioligand uptake and/or significant 
inflammation. In each region-of-interest, time-activity curve will be obtained from the dynamic 
PET image. Region uptake after blockade with celecoxib or after treatment will be expressed as a 
percentage of the baseline value. Possible difference of actual blood radioligand level may be 
adjusted by venous blood data obtained during the PET scans. 
Phase 3: The Quantitative measure of enzyme density (VT) in whole brain will be 
compared between patients and controls both at baseline and after celecoxib blockade. 
 
b. Power analysis  
Phases 1 and 2: This study is exploratory and we do not know how much would 
[11C]MC1 uptake be different between patients and healthy subjects. Thus, a formal power 
calculation is impossible. We wish to scan at least 10 subjects in each group of Phase 2 and 
request a maximum of 15 in each group to account for drop-outs. In total, we request permission 
to scan two subjects for Phase 1 and 60 subjects for Phase 2, for a total of 62 subjects. 
Phase 3 is also exploratory, and we request 12 RA patients and 22 healthy volunteers.  
Phase 4 is also exploratory, and we request 15 RA patients. 
11.  
HUMAN SUBJECTS PROTECTION 
a. 
Subject selection 
Participants will be selected based on the study's eligibility criteria. Participants will be 
admitted to the protocol regardless of gender, race, or ethnicity. NIMH employees/staff and their 
immediate family members will be excluded from the study per NIMH policy. 
 
b. Justification for exclusion of children  
Because this protocol has more than minimal risk from radiation exposure without 
possibility of direct benefit, inclusion of children is not appropriate. 
 
c. Justification for exclusion of other vulnerable subjects  
Pregnant women will be excluded because this protocol involves exposure to ionizing 
radiation. Lactating women will be excluded because radioisotopes may be excreted in milk. 
Persons with HIV infection are excluded to ensure that the results we see are related only to 
COX-2 binding and not to another abnormality such as a viral infection. 
 
d. Justification for sensitive procedures 
Not applicable 

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e. Safeguards for vulnerable populations and sensitive procedures 
Pregnancy testing will be performed before PET and MRI scanning for any participants 
of child-bearing potential. Protections for NIH employees and staff participating in this study 
include: 1) ensuring that participation or refusal to participate will have no effect, either 
beneficial or adverse, on the subject’s employment or position at the NIH, 2) giving employees 
and staff who are interested in participating the “NIH Frequently Asked Questions (FAQs) for 
Staff Who are Considering Participation in NIH Research” prior to obtaining consent, and 3) 
ensuring that there will be no direct solicitation of employees or staff. 
This study collects sensitive information. For example, we may collect information on 
drug and alcohol use, medical history and diagnoses. The PI will train study staff regarding 
obtaining and handling potentially sensitive and private information about co-workers through 
staff discussions and written branch/section procedures. 
12.  
BENEFIT/RISK  
a. Benefit 
This study offers no direct benefit to individual subjects but will lead to generalizable 
knowledge about RA, AxSpA, and myositis, and development of novel inflammatory 
biomarkers. 
13.  
CONSENT DOCUMENTS AND PROCESS 
Only the study investigators designated to obtain consent will be allowed to do so. All 
study investigators obtaining informed consent must have completed the NIMH HSPU training 
“Elements of Successful Informed Consent”.  
All participants will receive a verbal explanation in person and in the Clinical Center in 
terms suited to their comprehension of the purposes, procedures, and potential risks of the study 
and of their rights as research participants. Participants will have the opportunity to carefully 
review the written consent form and ask questions regarding this study prior to signing. To 
minimize undue coercion, participants may take as long as they wish to ask questions of anyone 
prior to signing. Consent may be obtained in-person or using NIH-approved telehealth platforms. 
The informed consent document will be provided as a physical or electronic document to 
the participant or consent designee as applicable for review prior to consenting. A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomfort and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to any research 
activities taking place. 
The initial consent process as well as re-consent, when required, may take place in person 
or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance 
with policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s). Whether in person or remote, the 
privacy of the subject will be maintained. Consenting investigators (and participant when in 
person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant will be informed of the private nature of the discussion and will be 
encouraged to relocate to a more private setting if needed. If the consent process is occurring 
remotely, participants and investigators will view individual copies of the approved consent 

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document on screens at their respective locations; the same screen may be used when both the 
investigator and the participant are co-located but this is not required. 
Note: When required, the witness signature will be obtained similarly as described for the 
investigator and participant below. 
When a hand signature on an electronic document is used for the documentation of 
consent, this study will use the following electronic platform to obtain the required signatures: 
• 
iMedConsent platform (which is 21 CFR Part 11 compliant) 
Both the investigator and the participant will sign the electronic document using a finger, 
stylus or mouse. Electronic signatures (i.e., the “signature” and a timestamp are digitally 
generated) will not be used. 
The consent process will be documented in CRIS. A copy of the consent form will be 
given to the participant and also uploaded in CRIS. 
14.  
DATA AND SAFETY MONITORING 
a. Data and safety monitor 
Data and safety will be monitored by an independent safety monitor (ISM) for this study: 
Dr. Peter Grayson. Dr. Grayson is a board-certified rheumatologist with full clinical privileges at 
the NIH Clinical Center. He runs the NIAMS Vasculitis Translational Research Program and 
relies heavily on advanced imaging for his work. He is also associated with the NIAMS Systemic 
Autoimmunity Branch (Kaplan Lab). His primary responsibility will be to provide independent 
safety monitoring in a timely fashion. 
 
b. Data and safety monitoring plan 
The PI will prepare a report on data and safety parameters for the ISM approximately 
every 12 months. The ISM will provide a written monitoring report to be submitted to the IRB at 
the time of continuing review. 
 
c. Criteria for stopping the study or suspending enrollment or procedures 
In the event of a serious adverse event related to the research, or if new data shed light on 
the danger of any procedures used, the study team, including the PI, will suspend further testing 
until the IRB and investigators have reviewed the safety information and determined whether to 
continue the study. 
 
15.  
QUALITY ASSURANCE (QA) 
a. Quality assurance monitor 
As per ICH-GCP 5.18 and FDA 21 CFR 312.50 clinical protocols are required to be 
adequately monitored. Monitoring for the NIH site will be conducted according to the “NIMH 
Intramural Program Guidelines for Monitoring of Clinical Trials”. Monitors under contract to 
the NIMH OCD ORO will visit the NIH site to monitor aspects of the study in accordance 
with the appropriate regulations and the approved protocol. The objectives of a monitoring 
visit will be:  1) to verify the existence of signed informed consent documents and 
documentation of the ICF process for each monitored subject; 2) to verify the prompt and 
accurate recording of all monitored data points, and prompt reporting of all SAEs; 3) to 
compare abstracted information from clinical databases (e.g. CTDB) with individual subjects’ 
records and source documents (subjects’ charts, laboratory analyses and test results, 

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physicians’ progress notes, nurses’ notes, and any other relevant original subject information); 
and 4) to help ensure investigators are in compliance with the protocol. The monitors also will 
inspect the clinical site regulatory files to ensure that regulatory requirements (Office for 
Human Research Protections-OHRP), FDA, and applicable guidelines (ICH-GCP) are being 
followed. During the monitoring visits, the investigator (and/or designee) and other study 
personnel will be available to discuss the study progress and monitoring visit. 
 
The investigator (and/or designee) will make study documents (e.g., consent forms, 
clinical database records and pertinent hospital/sources or clinical records readily available for 
inspection by the local IRB, FDA, the site monitors, and the NIMH staff for confirmation of the 
study data. 
 
A specific protocol monitoring plan will be discussed with the Principal Investigator and 
study staff. The plan will outline the frequency of monitoring visits based on such factors as 
study enrollment, data collection status and regulatory obligations. 
 
b. Quality assurance plan 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.   
Following written Standard Operating Procedures (SOPs), the monitors will verify that 
the clinical trial is conducted, and data are generated, and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonization Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
16.  
REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND 
PROTOCOL DEVIATIONS 
Reportable events for this protocol will be tracked and reported in compliance with 
Policy 801. 
It is both the Principal Investigator’s (PI) and the Sponsor’s responsibility to ensure the 
safety of those on the clinical trial.  The PI is responsible for tracking adverse events during the 
study and providing adverse events lists to the Sponsor at regular intervals per request. These 
may be requested quarterly and will be requested no less than once a year at the time of IND 
annual report to the FDA. ALL AEs that are collected, as determined by the written protocol, 
should be tracked in the ORSC RSS’ template AE Tracker or similar document. If the sponsor 
determines that adverse events are occurring more frequently or more severely than the written 
protocol had expected and/or anticipated, this should be submitted in an IND Safety Report, as 
described below.  In addition, the PI is responsible for updating the Sponsor about known risks 
from the drug, as discovered from literature searches or other means. 
In accordance with the requirements of 21 CFR 312.32, the PI or designee will report all 
SAEs, whether or not these are considered related to the investigational drug or study 
intervention, that occur throughout the study to the Sponsor, including those events listed in the 
protocol or Investigator’s Brochure as anticipated to occur, as follows:  
Deaths:  within 24 hours of the investigator’s * awareness 

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All other SAEs:  within 48 hours of the investigator’s* awareness 
All AEs will be sent to the Sponsor quarterly, unless requested more or less 
frequently, for submission to the FDA in the IND Annual Report. 
 
*“Investigator’s awareness” includes awareness by anyone on the study team. 
 
The PI will immediately report all deaths and SAEs to the Sponsor by disclosing all 
event-related information in a completed MedWatch Form 3500A. This form should include the 
IND number, protocol number, PI name, and an assessment on the reasonable possibility of a 
relationship between the event and the study drug or intervention. MRSs should NOT be 
included on this form. The completed MedWatch Form 3500A will be sent ENCRYPTED to 
the Clinical Director/CEO and/or designated medical monitor with a copy to the NIH Office of 
Research Support & Compliance (ORSC) Regulatory Support Section. 
The Clinical Director/CEO and/or designated medical monitor will be responsible for 
determining whether the event is reportable to the FDA as an IND Safety Report if it is a serious, 
unexpected, and suspected adverse reaction (SUSAR). If the sponsor determines the SAE meets 
the criteria of a SUSAR, the ORSC will submit an Initial IND Safety Report to the FDA no later 
than 15 calendar days after the PI’s notification of the event to the Sponsor. Deaths or life-
threatening events will be reported to the FDA no later than 7 calendar days after the PI’s 
notification of the event to the Sponsor. The Sponsor will submit any relevant additional 
information in a Follow-up IND Safety Report no later than 15 calendar days after receiving the 
information. All SAEs will be monitored until satisfactory resolution. All AEs and SAEs will be 
documented on appropriate study records. 
 
a.  For Research Radioligand Studied under IND 
The PI will report SAEs according to the requirements of 21 CFR 312.64(b). The PI will 
record nonserious AEs to the IRB at the time of Continuing Review, and to the Sponsor at 
regular intervals per request.  
17.  
ALTERNATIVES TO PARTICIPATION  
Subjects do not receive any treatment in this study or forego any treatment in order to 
participate in this study. The alternative, therefore, is not to participate. 
18.  
PRIVACY 
All research activities will be conducted in as private a setting as possible. 
19.  
CONFIDENTIALITY 
a. For research data and investigator medical records 
Data will be kept in password-protected computers. Only study investigators will have 
access to the data. This study collects sensitive medical information. The PI will train study staff 
regarding obtaining and handling potentially sensitive and private information about co-workers 
through staff discussions and written branch/section procedures. 
 
 
 

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b. For stored samples 
Blood samples will be discarded at the end of the PET scan. Data will be stored using 
codes that we assign.  
 
c. Special precautions 
Every necessary step will be taken to prevent identification of study participants and 
other violations of subject confidentiality. Information will be stored using a confidential case 
number, and no identifiers (name, address, phone number, etc.) will be used that could allow 
direct linking of database information to individual subjects. Where temporary linking of 
information with identifiers is needed, such identifiers will be temporarily attached to the data, 
and will be removed after information has been encoded. Secured e-mail will be used for all 
electronic communications of subject information between investigators. 
Demographic and clinical data will be archived in EXCEL on a password protected PC 
server and the Clinical Trial Database (CTDB). Clinical Safety Monitoring data will be archived 
together with other data. Laboratory test results will be stored on the CRIS. Only study 
investigators and internal/external monitors will have access to the samples and data. De-
identified results from this clinical trial will be posted on http://www.clinicaltrials.gov. 
20.  
CONFLICT OF INTEREST 
a. Distribution of NIH guidelines 
 
NIH guidelines on conflict of interest have been distributed to all investigators.  
b. Conflict of interest  
 
There are no conflicts-of-interest to report. 
21.  
RESEARCH AND TRAVEL COMPENSATION  
Study participants will be compensated for time and research-related inconveniences. 
Reimbursement is based on NIH standards for time devoted to the research project. Participants 
will be paid for each portion of the study they have completed whether or not they opt for early 
withdrawal from participation. Without any delay of study procedures or unanticipated 
inconvenience, the total possible compensation is $930. If the investigators need to delay study 
procedures or if additional time is needed for completion, subjects may receive additional 
compensation in accordance with NIH guidelines. Employees and staff who participate during 
work hours must have permission from their supervisor. NIH employees must either participate 
outside of work hours or take leave in order to receive compensation.   
 
Healthy volunteers undergoing dosimetry whole-body scan (Phase 1) 
Visit 1 to NIH 
 
PET scanning 
$150 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$10 
Total 
$200 

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Healthy volunteers undergoing whole-body scans with blocking studies (Phase 2) 
Visit 1 to NIH 
 
PET scanning x 2 
$500 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Celecoxib administration 
$50 
Total 
$610 
 
RA or patients undergoing whole-body scans with blocking studies (Phase 2) 
Visit 1 to NIH 
 
Clinical evaluation and 
screening procedures 
$90 
Escort fee 
$20 
Visit 2 to NIH 
 
PET scanning x 2 
$500 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Celecoxib administration 
$50 
Escort fee 
$20 
Total 
$740 
 
AxSpA patients undergoing whole-body scans with blocking studies (Phase 2) 
Visit 1 to NIH 
 
Clinical evaluation and 
screening procedures 
$90 
Escort fee 
$20 
Visit 2 to NIH 
 
 PET/MRI x2  
$700 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Celecoxib administration 
$50 
Escort fee 
$20 
Total 
$940 
 
IIM patients undergoing whole-body scans with blocking studies (Phase 2) 
Visit 1 to NIH 
 
Clinical evaluation and 
screening procedures 
$90 

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Escort fee 
$20 
Visit 2 to NIH 
 
PET scanning x 2 
$500 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Celecoxib administration 
$50 
Escort fee 
$20 
Visit to 3 to NIH 
 
MRI 
$100 
Pregnancy test 
$10 
Escort fee 
$20 
Total 
$ 870  
 
Healthy volunteers undergoing brain scans with blocking studies (Phase 3) 
Visit 1 to NIH 
 
PET scanning x 2 
$500 
Arterial catheter 
$60 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Celecoxib administration 
$50 
Visit 2 to NIH 
 
MRI 
$100 
Pregnancy test 
$10 
Total 
$780 
 
 
 
RA patients undergoing brain scans with blocking studies (Phase 3) 
Visit 1 to NIH 
 
Clinical evaluation and screening 
procedures 
$90 
Escort fee 
$20 
Visit 2 to NIH 
 
PET scanning x 2 
$500 
Arterial catheter 
$60 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Celecoxib administration 
$50 
Escort fee 
$20 
Visit 3 to NIH 
 
MRI 
$100 
Pregnancy test 
$10 

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Escort fee 
$20 
Total 
$ 930  
 
RA patients undergoing whole-body scans after treatment (phase 4) 
Visit 1 to NIH 
 
Clinical evaluation and 
screening procedures 
$90 
Escort fee 
$20 
Visit 2 to NIH 
 
PET scanning 
$250 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Escort fee 
$20 
Visit 3 to NIH 
 
PET scanning 
$250 
Antecubital venous catheters 
$30 
Pregnancy test 
$10 
Movement restriction 
$20 
Escort fee 
$20 
Total 
$770 
NIH will cover travel expenses to the Clinical Center for all participants in accord with 
NIH guidelines.  
 
 

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22.  
REFERENCES 
Aisen PS, Thal LJ, Ferris SH, Assaid C, Nessly ML, Giuliani MJ, et al. Rofecoxib in patients 
with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial. 
Current Alzheimer research 2008; 5(1): 73-82. 
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 
Rheumatoid arthritis classification criteria: an American College of Rheumatology/European 
League Against Rheumatism collaborative initiative. Arthritis and rheumatism 2010; 62(9): 
2569-81. 
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). The New England 
journal of medicine 1975a; 292(7): 344-7. 
Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). The New England 
journal of medicine 1975b; 292(8): 403-7. 
Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: 
implications for translational research. Trends in pharmacological sciences 2009; 30(4): 174-81. 
Crofford LJ, Wilder RL, Ristimaki AP, Sano H, Remmers EF, Epps HR, et al. Cyclooxygenase-
1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, 
and corticosteroids. The Journal of clinical investigation 1994; 93(3): 1095-101. 
Elzinga EH, van der Laken CJ, Comans EF, Lammertsma AA, Dijkmans BA, Voskuyl AE. 2-
Deoxy-2-[F-18]fluoro-D-glucose joint uptake on positron emission tomography images: 
rheumatoid arthritis versus osteoarthritis. Molecular imaging and biology : MIB : the official 
publication of the Academy of Molecular Imaging 2007; 9(6): 357-60. 
Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et al. Celecoxib versus 
diclofenac in long-term management of rheumatoid arthritis: randomised double-blind 
comparison. Lancet (London, England) 1999; 354(9196): 2106-11. 
Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ. Efficacy of rofecoxib, celecoxib, and 
acetaminophen in osteoarthritis of the knee: a randomized trial. Jama 2002; 287(1): 64-71. 
Kang YJ, Mbonye UR, DeLong CJ, Wada M, Smith WL. Regulation of intracellular 
cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 2007; 46: 
108-25. 
Korotkova M, Helmers SB, Loell I, Alexanderson H, Grundtman C, Dorph C, et al. Effects of 
immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases 
expression in muscle tissue of patients with polymyositis or dermatomyositis. Annals of the 
rheumatic diseases 2008; 67(11): 1596-602. 
Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, et al. A genetic polymorphism 
for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human 
brain to this putative biomarker of neuroinflammation. Journal of cerebral blood flow and 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 38 of 40 
metabolism : official journal of the International Society of Cerebral Blood Flow and 
Metabolism 2013a; 33(1): 53-8. 
Learn CA, Mizel SB, McCall CE. mRNA and protein stability regulate the differential 
expression of pro- and anti-inflammatory genes in endotoxin-tolerant THP-1 cells. J Biol Chem 
2000; 275: 12185-93. 
Lloyd TE, Mammen AL, Amato AA, Weiss MD, Needham M, Greenberg SA. Evaluation and 
construction of diagnostic criteria for inclusion body myositis. Neurology 2014; 83(5): 426-33. 
Lockwood AH. Invasiveness in studies of brain function by positron emission tomography 
(PET). J Cereb Blood Flow Metab 1985; 5: 487-9. 
McCann NC, Lynch TJ, Kim SO, Duffy DM. The COX-2 inhibitor meloxicam prevents 
pregnancy when administered as an emergency contraceptive to nonhuman primates. 
Contraception 2013; 88(6): 744-8. 
McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus 
diclofenac in the management of osteoarthritis of the knee: a placebo-controlled, randomised, 
double-blind comparison. Scand J Rheumatol 2001; 30(1): 11-8. 
Motsko SP, Rascati KL, Busti AJ, Wilson JP, Barner JC, Lawson KA, et al. Temporal 
Relationship between Use of NSAIDs, Including Selective COX-2 Inhibitors, and 
Cardiovascular Risk. Drug Safety 2006; 29(7): 621-32. 
Orjales A, Mosquera R, López B, Olivera R, Labeaga L, Núñez MT. Novel 2-(4-
methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors. 
Bioorganic & Medicinal Chemistry 2008; 16(5): 2183-99. 
Paulson SK, Vaughn MB, Jessen SM, Lawal Y, Gresk CJ, Yan B, et al. Pharmacokinetics of 
celecoxib after oral administration in dogs and humans: effect of food and site of absorption. The 
Journal of pharmacology and experimental therapeutics 2001; 297(2): 638-45. 
Pelliccia F, Pasceri V, Granatelli A, Pristipino C, Speciale G, Roncella A, et al. Safety and 
efficacy of short-term celecoxib before elective percutaneous coronary intervention for stable 
angina pectoris. The American journal of cardiology 2006; 98(11): 1461-3. 
Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. 
Modified disease activity scores that include twenty-eight-joint counts. Development and 
validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis 
Rheum 1995; 38(1): 44-8. 
Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal 
toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid 
arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety 
Study. Jama 2000; 284(10): 1247-55. 

Abbreviated Title: PET in MSK Conditions 
Version Date: 04/16/24 
 
 
 
 
page 39 of 40 
Steiner G, Tohidast-Akrad M, Witzmann G, Vesely M, Studnicka-Benke A, Gal A, et al. 
Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford, 
England) 1999; 38(3): 202-13. 
Studynkova JT, Kuchen S, Jeisy E, Schedel J, Charvat F, Jarosova K, et al. The expression of 
cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase in inflammatory muscle tissue of 
patients with polymyositis and dermatomyositis. Clinical and experimental rheumatology 2004; 
22(4): 395-402. 
Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, et al. Analysis of the synovial 
cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis and 
rheumatism 1997; 40(2): 217-25. 
The Alzheimer's Disease Anti-inflammatory Prevention Trial Research G. Results of a follow-up 
study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT). 
Alzheimer's & Dementia 2013; 9(6): 714-23. 
Tsuji S, Miyoshi H, Tomita T, Nakase T, Hamada M, Oomae T, et al. Celecoxib, a 
cyclooxygenase-2 inhibitor, improved upper gastrointestinal lesions in rheumatoid arthritis 
patients as assessed by endoscopic evaluation. Modern rheumatology 2012; 22(3): 353-62. 
Zanotti-Fregonara P, Innis RB. Suggested pathway to assess radiation safety of 11C-labeled PET 
tracers for first-in-human studies. Eur J Nucl Med Mol Biol 2012; 39: 396-8. 
 
 
 

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Appendix 1. ASAS Criteria for Axial Spondyloarthritis. 
Patients with back pain for ≥3 months duration, and who are <45 years of age, are 
considered to have Axial Spondyloarthritis (Axial SpA) if they have either (1) sacroiliitis on 
imaging and one or more features of SpA, or (2) HLA-B27 and 2 or more features of SpA. 
Sacroiliitis on imaging is defined as active inflammation on MRI highly suggestive of sacroiliitis 
associated with SpA, or definite radiographic sacroiliitis according to the modified NY criteria. 
Features of SpA include (a) IBP, (b) arthritis, (c) enthesitis in the heel, (d) uveitis, (e) dactylitis, 
(f) psoriasis, (g) IBD, (h) a good response to an NSAID, (i) positive family history of SpA, (j) 
HLA-B27, and (k) elevated CRP.