Conditions: Healthy
Keywords: PET Imaging Neuroinflammation Tspo
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: yes

Brief summary:
Background:

Inflammation in the brain plays a role in many diseases. Being able to measure inflammation in a person's brain might help to diagnose and treat these diseases. One protein (TSPO) appears in higher numbers when inflammation affects the brain. To see TSPO when a person's body is scanned, researchers need a substance called a radiotracer that will attach to this protein and no other molecules.

Objective:

This study will test whether a new radiotracer (\[18F\]SF12051) can make TSPO appear on PET scans of a person's brain and body.

Eligibility:

Healthy people aged 18 and older.

Design:

This study requires 2 to 4 visits to the clinic.

All participants will be screened. They will have a physical exam. They will have blood tests and a test of their heart function.

Some participants will have a positron emission tomography (PET) scan of the whole body. The radiotracer will be injected through a tube (catheter) placed in a vein in the arm. The PET scanner is a machine shaped like a doughnut. Participants will lie on a bed that slides in and out of the scanner. The scan will take about 2 hours.

Some participants will have a PET scan of just their head. After they are injected with the radiotracer, they will lie on a bed with their head in the scanner. Blood will be drawn from a catheter in the wrist during the scan.

Some participants will have a magnetic resonance imaging (MRI) scan of the brain. They will lie on a narrow bed that slides into a tube.

Detailed description:
Study Description:

This study is intended to provide information on the novel \[18F\]SF12051 radioligand and its ability to localize and measure TSPO in the brain and body of healthy individuals.

Objectives:

Primary Objective: To study the brain uptake of \[18F\]SF12051 and perform kinetic modeling of the \[18F\]SF12051 in the three different TSPO genotypes.

Secondary Objectives: To study the brain retest characteristics, biodistribution and dosimetry of \[18F\]SF12051 in healthy subjects.

Endpoints:

Primary Endpoint: The distribution volume of the radioligand and stability over time calculated with compartmental modeling, attention paid to differences in mean distribution volumes between TSPO genotypes for determining genotype sensitivity.

Secondary Endpoints: Retest variability and reliability and organ time- activity curves to determine biodistribution and dosimetry.

Arms:
arm 1: Healthy participants with HAB TSPO genotype receive 18F-SF12051 intravenously followed by whole body or brain positron emission tomography (PET) scan. Participants were randomized to either phase 1, 2, or 3. Phases 1 \& 3 had whole body PET scan and phase 2 had brain PET scan. arm 2: Healthy participants with LAB TSPO genotype receive 18F-SF12051 intravenously followed by whole body or brain positron emission tomography (PET) scan. Participants were randomized to either phase 1, 2, or 3. Phases 1 \& 3 had whole body PET scan and phase 2 had brain PET scan. arm 3: Healthy participants with MAB TSPO genotype receive 18F-SF12051 intravenously followed by whole body or brain positron emission tomography (PET) scan. Participants were randomized to either phase 1, 2, or 3. Phases 1 \& 3 had whole body PET scan and phase 2 had brain PET scan.

Interventions: intervention 1: 18F-SF12051
Intervention descriptions: intervention 1: Injected intravenously followed by PET scanning

Protocol document:
Prot_SAP_000.pdf: 
1
Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
Abbreviated Title: [18F]SF12051 in Healthy Subjects
NIH IRB:  000674
Version Date:  12/05/23
Title: Assessment of [18F]SF12051 for Imaging the 18-kDa Translocator Protein (TSPO) in 
Brain and Whole Body of Healthy Subjects
NIH Principal Investigator:
Robert Innis, M.D., Ph.D.
Molecular Imaging Branch
National Institute of Mental Health
Building 10, Rm B1D43
9000 Rockville Pike
Bethesda, MD 20892
Phone: 301.594.1368
E-mail: robert.innis@nih.gov
Investigational Agents:
Drug Name:
[18F]SF12051
IND Number:
162310
Sponsor:
NIMH IRP
Manufacturer:
NIMH IRP


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................2
STATEMENT OF COMPLIANCE ................................................................................................6
1
PROTOCOL SUMMARY.......................................................................................................7
1.1
Synopsis ............................................................................................................................7
1.2
Schema..............................................................................................................................8
1.3
Schedule of Activities (SOA) ...........................................................................................9
2
INTRODUCTION .................................................................................................................10
2.1
Study Rationale...............................................................................................................10
2.2
Background .....................................................................................................................10
2.2.1
Scope of Study.........................................................................................................10
2.2.2
[18F]SF12051 as a TSPO Radioligand in Mice and Rhesus Monkeys ....................12
2.3
Risk/Benefit Assessment.................................................................................................14
2.3.1
Known Potential Risks ............................................................................................14
2.3.2
Known Potential Benefits........................................................................................16
2.3.3
Assessment of Potential Risks and Benefits............................................................16
3
OBJECTIVES AND ENDPOINTS.......................................................................................16
4
STUDY DESIGN ..................................................................................................................17
4.1
Overall Design ................................................................................................................17
4.2
Scientific Rationale for Study Design.............................................................................17
4.3
Justification for Dose ......................................................................................................17
5
STUDY POPULATION........................................................................................................17
5.1
Inclusion Criteria.............................................................................................................17
5.2
Exclusion Criteria ...........................................................................................................18
5.3
Inclusion of Vulnerable Participants...............................................................................18
5.3.1
Participation of NIH Staff or family members of study team members..................18
5.4
Lifestyle Considerations .................................................................................................19
5.5
Screen Failures................................................................................................................19
5.6
Strategies for Recruitment and Retention .......................................................................19
5.6.1
Costs ........................................................................................................................20
5.6.2
Compensation ..........................................................................................................20
6
STUDY INTERVENTION ...................................................................................................22


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
6.1
Study Interventions(s) Administration............................................................................22
6.1.1
Study Intervention Description................................................................................22
6.1.2
Dosing and Administration......................................................................................22
6.2
Preparation/Handling/Storage/Accountability................................................................22
6.2.1
Acquisition and Accountability ...............................................................................22
6.2.2
Formulation, Appearance, Packaging, and Labeling...............................................22
6.2.3
Product Storage and Stability ..................................................................................23
6.2.4
Preparation...............................................................................................................23
6.3
Measures to Minimize Bias: Randomization and Blinding ............................................23
6.4
Study Intervention Compliance ......................................................................................23
6.5
Concomitant Therapy......................................................................................................23
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .....................................................................................23
7.1
Discontinuation of Study Intervention............................................................................23
7.2
Participant Discontinuation/Withdrawal from the Study................................................24
7.3
Lost to Follow-up............................................................................................................24
8
STUDY ASSESSMENTS AND PROCEDURES.................................................................24
8.1
Screening Procedures......................................................................................................24
8.1.1
Screening activities performed prior to obtaining performed consent ....................24
8.1.2
Screening activities performed after a consent for screening has been signed........25
8.2
Study Evaluations & Procedures.....................................................................................25
8.2.1
PET Procedures .......................................................................................................25
8.2.2
Clinical Evaluations.................................................................................................27
8.2.3
Biospecimen Evaluations.........................................................................................27
8.2.4
Correlative Studies for Research/Pharmacokinetic Studies ....................................27
8.2.5
Samples for Genetic/Genomic Analysis..................................................................27
8.3
Safety and Other Assessments ........................................................................................27
8.4
Adverse Events and Serious Adverse Events .................................................................28
8.4.1
Definition of Adverse Event....................................................................................28
8.4.2
Definition of Serious Adverse Events (SAE) ..........................................................28
8.4.3
Classification of an Adverse Event..........................................................................28
8.4.4
Time Period and Frequency for Event Assessment and Follow-Up........................29


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
8.4.5
Adverse Event Reporting.........................................................................................30
8.4.6
Serious Adverse Event Reporting............................................................................30
8.4.7
NIH Intramural IRB Reporting of IND Safety Reports...........................................31
8.4.8
Events of Special Interest ........................................................................................31
8.4.9
Reporting of Pregnancy ...........................................................................................31
8.5
Unanticipated Problems ..................................................................................................31
8.5.1
Definition of Unanticipated Problems (UP) ............................................................31
8.5.2
Unanticipated Problem Reporting ...........................................................................31
9
STATISTICAL CONSIDERATIONS ..................................................................................31
9.1
Statistical Hypothesis......................................................................................................31
9.2
Sample Size Determination.............................................................................................32
9.3
Populations for Analyses ................................................................................................32
9.3.1
Evaluable for toxicity ..............................................................................................32
9.3.2
Evaluable for objective response.............................................................................32
9.3.3
Evaluable Non-Target Disease Response................................................................32
9.4
Statistical Analyses .........................................................................................................32
9.4.1
General Approach....................................................................................................32
9.4.2
Analysis of the Primary Endpoints..........................................................................33
9.4.3
Analysis of the Secondary Endpoint(s) ...................................................................33
9.4.4
Safety Analyses .......................................................................................................33
9.4.5
Baseline Descriptive Statistics.................................................................................33
9.4.6
Planned Interim Analyses........................................................................................33
9.4.7
Sub-Group Analyses................................................................................................33
9.4.8
Tabulation of individual Participant Data................................................................33
9.4.9
Exploratory Analyses...............................................................................................33
10
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................33
10.1
Informed Consent Process...........................................................................................33
10.1.1
Consent/Assent Procedures and Documentation.....................................................33
10.1.2
Consent for minors when they reach the age of majority........................................34
10.1.3
Considerations for Consent of NIH staff, or family members of study team 
members.................................................................................................................................34
10.1.4
Consent of Subjects who are, or become, decisionally impaired ............................34


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Version Date: 12/05/23
10.2
Study Discontinuation and Closure.............................................................................34
10.3
Confidentiality and Privacy.........................................................................................35
10.4
Future use of Stored Specimens and Data...................................................................35
10.5
Safety Oversight..........................................................................................................36
10.6
Clinical Monitoring .....................................................................................................36
10.7
Quality Assurance and Quality Control ......................................................................37
10.8
Data Handling and Record Keeping............................................................................37
10.8.1
Data Collection and Management Responsibilities.................................................37
10.8.2
Study Records Retention .........................................................................................37
10.9
Protocol Deviations and Non-Compliance..................................................................37
10.9.1
NIH Definition of Protocol Deviation .....................................................................38
10.10
Publication and Data Sharing Policy...........................................................................38
10.10.1 Human Data Sharing Plan .......................................................................................38
10.10.2 Genomic Data Sharing Compliance ........................................................................38
10.11
Conflict of Interest Policy ...........................................................................................38
11
ABBREVIATIONS ...............................................................................................................39
12
REFERENCES ......................................................................................................................40


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Title:
Assessment of [18F]SF12051 for Imaging the 18-kDa Translocator 
Protein (TSPO) in Brain and Whole Body of Healthy Subjects
Study Description:
This study is intended to provide information on the novel 
[18F]SF12051 radioligand and its ability to localize and measure 
TSPO in the brain and body of healthy individuals.
Objectives:
Primary Objective:  To study the brain uptake of [18F]SF12051 
and perform kinetic modeling of the [18F]SF12051 in the three 
different TSPO genotypes.
Secondary Objectives: To study the brain retest characteristics, 
biodistribution and dosimetry of [18F]SF12051 in healthy subjects.  
Endpoints:
Primary Endpoint: The distribution volume of the radioligand and 
stability over time calculated with compartmental modeling, 
attention paid to differences in mean distribution volumes between 
TSPO genotypes for determining genotype sensitivity. 
Secondary Endpoints: Retest variability and reliability and organ-
time-activity curves to determine biodistribution and dosimetry.
Study Population:
Up to forty-five (45) healthy male and female volunteers (18 years 
and older) of the three different TSPO genotypes for brain and 
whole-body imaging.
Phase:
N/A
Description of 
Sites/Facilities 
Enrolling Participants:
Screening and PET imaging will be performed at the NIH Clinical 
Center.    
Description of Study 
Intervention:
Arterial line, PET scan, and brain MRI scan for absolute 
quantification of TSPO. Blood drawn from all subjects to 
determine TSPO genotype.
Study Duration:
3 years
Participant Duration:
1-4 visits, 2-6 hours per visit.


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
1.2
SCHEMA
Prior to 
Enrollment 
•Assessment of medical records and screened for TSPO binding 
genotype under protocol 01M0254  “The Evaluation of Patients 
with Mood and Anxiety Disorders and Healthy Participants”
Phase 1
• 1st visit:   Screening
• 2nd visit: Pregnancy test; whole body PET scan (5 hours)
Phase 2
• 1st visit:   Screening 
• 2nd visit: Pregnancy test; brain PET scan (6 hours)
• 3rd visit: Pregnancy test; MRI (2 hours)
Phase 3
• 1st visit:   Screening
• 2nd visit: Pregnancy test; whole body PET scan (5 hours)
Phase 4
• 1st visit:   Screening
• 2nd visit: Pregnacy test; brain PET scan (6 hours)
• 3rd visit: Pregnancy test; MRI (2 hours)
• 4th visit: Pregnancy test; retest brain PET (6 hours)


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
 Schedule of Activities (SOA)
This study will require 1-4 visits for each participant depending on the phase in which they are 
in. An initial blood sample to determine TSPO binding genotype will be acquired under protocol 
01-M-0254 “The Evaluation of Patients with Mood and Anxiety Disorders and Healthy 
Participants”. The first visit for each phase will encompass a screening evaluation that includes 
H&P, lab tests and EKG. Subsequent visits will include an MRI and/or a PET scan, in order of 
earliest availability, and arterial line for the volunteers in the primary study with brain PET 
scans. If possible, MRI and PET scans can be done on the same day to limit to two or three total 
visits. The MRI and PET visits will take approximately 2 and 6 hours, respectively. For 
dosimetry, two total visits are sufficient due to lack of MRI.
This protocol is a first-in-human evaluation of [18F]SF12051 and has four phases:
a) Phase 1: whole body PET imaging of one [1] subject with a low injection activity of ~2 
mCi to confirm that no organ has prominently high uptake of [18F]SF12051;
b) Phase 2: kinetic brain PET imaging in ten [10] subjects with up to 5 mCi injection to 
quantify TSPO in brain relative to concurrent measurement of the parent radioligand in 
arterial plasma;
c) Phase 3: if [18F]SF12051 is successful in Phase 2 in the first couple of subjects, we will 
estimate the radiation-absorbed doses by performing whole body PET imaging on up to 
ten  [10] subjects, with 5 mCi injection;
d) Phase 4: test-retest brain PET analysis in up to twenty-four [24] subjects, of brain binding 
relative to concurrent measurement of the parent radioligand in arterial plasma (5 mCi 
per scan).
Thus, a total of 11 participants for whole body imaging and 34 participants for brain 
imaging.
Table 1 for Phases 1 and 3
* The screening lab tests are described in Section 8.1.2.
** Safety tests for each PET scan are described in Section 8.3
1st Visit / 
Screen
2nd Visit
Informed Consent
X
History and physical exam
X
Screening lab tests*
X
EKG
X
X
Pregnancy test (female 
subjects)
x
X
Whole-body PET with 
venous sampling
X
Safety tests for PET scans**
X
Follow-up phone call
X


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
Table 2 for Phases 2 and 4
* The screening lab tests are described in Section 8.1.2.
** Safety tests for each PET scan are described in Section 8.3
If the MRI can be performed on the day of a PET scan, the number of visits will be reduced.
2
INTRODUCTION
2.1
STUDY RATIONALE
The mitochondrial protein 18-kDa translocator protein (TSPO) is highly expressed in 
phagocytic inflammatory cells, including activated microglia and reactive astrocytes in the brain 
and macrophages in the periphery (1,2). Although numerous positron emission tomography 
(PET) radioligands have been developed to image TSPO, several limitations have restricted their 
clinical utility for quantifying inflammation in the brain. Of these radioligands, the first-
generation TSPO radioligand 11C-(R)-PK11195 has been the most extensively studied. 11C-(R)-
PK11195 has high affinity to TSPO; however, its utility is limited by low ratio of specific-to-
nondisplaceable uptake (i.e., nondisplaceable binding potential, BPND) in the brain as well as the 
relatively short half-life of 11C (20 minutes) (3,4). Second-generation radioligands, such as 11C-
PBR28, offer a higher in vivo TSPO-specific signal but suffer from sensitivity to the single 
nucleotide polymorphism (SNP) rs6971 (5,6), which splits the human population into high-, 
mixed-, and low-affinity binders (HAB, MAB, LAB). LAB have too little TSPO binding to 
measure. This SNP sensitivity both complicates the interpretation of results and requires 
genotyping of study participants to exclude LABs before imaging. 
Recently, we synthesized a new TSPO ligand, [11C]ER176, which, although still sensitive 
to genotype differences, has enough specific binding to allow the imaging of low binders as well 
(7). This has important practical advantages, because low binders would not need to be excluded 
from clinical protocols and genotyping could be performed at the end of the protocol for all 
subjects at once, rather than case-by-case before scanning takes place. However, ER176 is 
labeled with 11C, and therefore would not be available to centers without a cyclotron on site. The 
rationale of this study is to determine whether a novel 18F-labeled radioligand, [18F]SF12051, 
1st Visit / 
Screen
2nd Visit
3rd Visit
4th Visit
Informed Consent
X
History and physical exam
X
Screening lab tests*
X
Pregnancy test (female 
subjects)
X
X
X
X
EKG
X
X
X
Brain MRI
X
Brain PET with arterial 
sampling
X
X
Safety tests for PET scans**
X
X
Follow-up phone call
X
X


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
whose structure is similar to that of [11C]ER-176, has comparable or improved efficacy for 
imaging TSPO and/or dependence on TSPO genotype.
We predict that the new 18F-radioligand will be like [11C]ER176 and, therefore, that it will 
be sensitive to genotype. Even though [11C]ER176 is sensitive to genotype, it provides time-
stable values of receptor binding. Thus for [11C]ER176 and presumably for [18F]SF12051, LAB 
subjects need not be excluded a priori, but the results must be corrected a posteriori. If 
[18F]SF12051 values of receptor binding are unstable in LABs, it would still be an improvement 
over current 11C-rdaioligands and can be used at more sites because of the longer half-life of 18F 
compared to 11C.”
2.2
BACKGROUND
2.2.1
Scope of Study
The 18 kDa translocator protein (TSPO) is found on the membrane of mitochondria, and 
in the brain is primarily located in microglia and astrocytes, cell types typically activated during 
inflammation. Inflammation has been suggested to be a facet of many neurological disorders, 
giving the possibility of in vivo measurements significance in terms of furthering understanding 
the physiology of and diagnosing these diseases. Upon activation, microglial expression of TSPO 
expression increases significantly, implicating it in the process of neuroinflammation (8). Due to 
the phenomenon, TSPO has been suggested as a good in vivo biomarker for measuring 
neuroinflammation on the assumption that increased TSPO binding sites would indicate an 
increase in activated microglia, and thus in inflammation (9). A key method to do this 
measurement is to use radiotracers during positron emission tomography (PET) scans that can 
cross the blood brain barrier and bind to TSPO. The first radiotracer developed for TSPO, 
[11C]PK11195, has issues of high non-specific binding and poor signal-to-noise ratio resulting in 
a lack of stable quantitative analysis, driving research to look for an alternative. 
A significant factor to consider in developing and employing TSPO radioligands is the 
presence of a single nucleotide polymorphism in the TSPO gene. This polymorphism divides 
populations into three genetic groups: high-affinity binders (HABs), mixed-affinity binders 
(MABs), and low-affinity binders (LABs). The development of the most recent third generation 
TSPO radioligand, [11C]ER176 sought to overcome these challenges to provide better in vivo 
imaging data. While an in-human study showed consistently quantifiable distribution volume for 
TSPO with [11C]ER176 than its predecessor in all three genetic groups, there was still some 
genetic preference for HABs as compared to MABs or LABs (7). Despite this residual sensitivity 
to genotype, this new ligand allows for the inclusion of all three genetic types into future TSPO 
studies. 
In contrast to carbon-11, fluorine-18 has several beneficial characteristics for clinical 
PET imaging. Its relatively longer half-life (~110 versus ~20 minutes) allows imaging for a 
longer period of time and broader distribution of the radioligand from a central radiopharmacy, 
giving 18F-labeled radioligands greater flexibility for widespread use. Unfortunately, ER176 does 
not contain a fluorine atom and cannot be easily labeled with fluorine-18. To address this issue, 
our laboratory synthesized six new fluorine-containing analogs of ER176 as candidate 
compounds for 18F-radiolabeling—three isomers with a fluoro group and three with a 
trifluoromethyl group at each of three positions (ortho, meta, and para) of the pendant aryl ring 
(Figure 1). In vitro studies demonstrated that all six analogs had high affinity for human TSPO 


12
Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
(Ki = 1.2−7.0 nM) and could be successfully labeled with carbon-11 with good yield (66–81%) 
and excellent chemical (>95%) and radiochemical purities (> 99%). Of these six, the most 
promising for 18F-labeling was SF12051, which was then evaluated in mice and monkeys (See 
Section 2.2.2).
Figure 1. Chemical structures of ER176 and six fluorine-containing analogs.
The objective of this first-in-human study is evaluation of [18F]SF12051 as a TSPO 
radioligand, specifically looking at its distribution volume values, stability over time, and how 
uptake varies between the three genetic binding affinities. The expectation for this study is that 
the [18F]SF12051 radioligand will exhibit characteristics like [11C]ER176. If found to be 
successful, the [18F]SF12051 radioligand would be a more widely useful tracer for TSPO in vivo 
studies
2.2.2
 [18F]SF12051 as a TSPO Radioligand in Mice and Rhesus Monkeys
To warrant this human study, first research was done to evaluate the effectiveness of 
[18F]SF12051 in mice and rhesus monkeys. Use of [18F]SF12051 in mice showed high brain 
uptake and subsequent strong signal blockade by PK11195, a TSPO-specific blocking agent, 
suggesting that the radioligand was binding specifically to TSPO in the mouse brain. 


13
Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
Figure 2. Left panel: Baseline (blue) and blocked (red) curves of [18F]SF12051 in rat. Right 
panel: administration of PK11195 blocked 79% of the signal in the brain.
Following its success in mice, [18F]SF12051 was then evaluated in a rhesus macaque. 
Results showed typical time-activity curves for baseline and blocked scans and good time-
stability of the ligand after sixty minutes of scanning. The uptake of the radioligand was 
significantly displaced by administration of PK11195, suggesting specific TSPO binding in 
monkey brain. These results suggest that [18F]SF12051 will be able to specifically bind to TSPO 
in human brain and warrants further investigation.
Figure 3. Left panel: Baseline (blue) and blocked (red) curves of [18F]SF12051 in monkey. Right 
panel: time-stability analysis, which shows that stable VT is reached at about 60 minutes.
Blocking Effect: 79%
0
5
10
15
BLK (n=1)
BL (n=3)
SUV (100-120 min)
0
30
60
90
120
0
1
2
3
AVG BLK (n=1)
AVG BL (n=3)
Tme (min)
Conc radioactivity (SUV)
Time-Activity Curves
0
30
60
90
120
150
180
0
1
2
3
18F_BL
18F_BLK
Time (min)
Conc. radioactivity (SUV)
Time-Activity Curves
0
60
120
180
0.6
0.8
1.0
1.2
1.4
Frontal
Cingulate
Striatum
Temporal
Parietal
Occipital
Cerebellum
Insula
Amygdala
Hippocampus
Thalamus
Scan Duration (min)
Normalized VT
Time-Stability 


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Abbreviated Title: [18F]SF12051 in Healthy Subjects
Version Date: 12/05/23
Figure 4. Baseline (top) and blocked (bottom) images show uptake of [18F]SF12051 in rhesus 
macaque brain before and after administration of PK11195.
2.3
RISK/BENEFIT ASSESSMENT
2.3.1
Known Potential Risks
Potential risks from this study include those associated with: a) medical examinations 
including phlebotomy for blood and urine analysis, b) radiation exposure from the PET and 
transmission scans, c) PET scanning, d) placement of arterial or venous lines, e) blood sampling, 
f) MRI, and g) ECG.
2.3.1.1 Medical Examinations
Medical examinations, including phlebotomy for blood analysis are not associated with 
more than minimal risks. There is usually some discomfort when the needle is inserted for 
phlebotomy.  
2.3.1.2 Radiation Exposure
Radiation exposure in this protocol will be from [18F]SF12051 and the associated 
transmission scans. With our PET/CT scan, the effective doses for one head and one whole-body 
transmission scans 0.02 and 0.6 rem respectively. In addition, we routinely include the dose from 
two transmission scans in the event that it must be repeated in a subject. The effective dose from 
two head CT scans is 0.04 rem (and from four CT scans in case of test-retest acquisition is 0.08 
rem) and from two whole body scans is 1.2 rem. The radiation exposure from [18F]SF12051 is 
unknown, but 18F-labeled compounds generally show very similar dosimetric values of about 20 
µSv/MBq (0.074 rem/mCi) (10) or about 0.37 rem for a 5 mCi injection.
Please note that no pharmacological effects are expected from [18F]SF12051. Therefore, only 
radiation risks are relevant to this tracer.
2.3.1.3 PET Scanning
PET scans, which detect injected radioactivity within the body, are not associated with 
any known physical hazards to the participant lying on the table. We routinely use a series of 
procedures to minimize the risk of discomfort during scanning sessions. The procedures are 
Baseline
Blocked


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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.
2.3.1.4 Arterial and/or Venous Line Placement
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. 
Arterial catheterization is a generally safe and reliable method of obtaining arterial blood 
samples (11). 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.
2.3.1.5 Blood Sampling
Participants may have arterial or venous blood sampling. The total amount of blood 
drawn shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week 
period. 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 participant. 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 eight weeks before the 
study or for eight weeks following the study.  
2.3.1.6 MRI
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, an 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. Participants will be screened 
again for these conditions before having any scan and will not receive an MRI scan if they have 
any contraindications. 
It is not known whether MRI is completely safe for a developing fetus. Therefore, all 
women of childbearing potential will have a urine pregnancy test performed no more than 24 
hours before each MRI scan. The scan will not be done if the pregnancy test is positive. 
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. Participants will be 


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asked to complete an MRI screening form for each MRI scan they have. There are no known 
long-term risks associated with MRI scans.
2.3.1.7 EKG
The patient may feel uncomfortable while the electrodes are attached to the chest. The 
conductive gel sometimes causes some mild irritation.
2.3.2
Known Potential Benefits
This study offers no direct benefits to participants. Information obtained from this protocol study 
may improve our understanding of the pharmacokinetics and usefulness of a new TSPO tracer. 
2.3.3
Assessment of Potential Risks and Benefits
This study will determine the viability of [18F]SF12051 as a prominent radiotracer for TSPO in 
vivo imaging. If successful, this radiotracer can be a more stable alternative for future TSPO 
imaging studies as compared to the currently used 11C counterpart. The risks are reasonable in 
relation to anticipated benefit. 
The ways in which the study design aims to minimize risks, please reference each risk 
detailed above (see Section 2.3.1). 
3
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To evaluate the brain uptake of 
[18F]SF12051 in healthy volunteers and 
perform kinetic modeling of the 
[18F]SF12051 in the three different 
TSPO genotypes
Receptor density measured as 
distribution volume (VT) 
VT is the ‘gold 
standard’ method to 
measure receptor 
density.
Secondary
To study retest variability and 
reliability of [18F]SF12051
Receptor density measured as 
distribution volume (VT) 
The two key 
parameters for retest 
studies are variability 
and reliability.
To study the biodistribution and 
dosimetry of [18F]SF12051 in 
healthy subjects
Radiation burden to organs of the 
body
We follow the FDA 
standards for 
calculating radiation 
burden.


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4
STUDY DESIGN
4.1
OVERALL DESIGN

Site: This single-site study will be conducted at the NIH Clinical Center.

Hypothesis: We hypothesize that [18F]SF12051 will have satisfactory distribution 
regardless of genotype, acceptable retest variability and reliability, and dosimetry 
typical of 18F-labeled radioligands.

Phase: Phase 1

Type of Design: Study is neither randomized nor placebo-controlled; exploratory 
study.

Study Groups: Healthy volunteers

Study intervention: Brain and body PET scans with [18F]SF12051 and brain MRI.

Interim Analysis: None

Stratifications: None
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
This study is to evaluate the efficacy of a novel radioligand and could provide useful information 
for other studies investigating TSPO in the future.
4.3
JUSTIFICATION FOR DOSE
Studies with novel 18F-radioligands typically inject 5 mCi i.v., which is enough to measure both 
radioactivity in brain with PET and the concentration of parent radioligand in arterial plasma.
5
STUDY POPULATION
5.1
INCLUSION CRITERIA
To be eligible to participate in this study, an individual must meet all of the following criteria:
1. Aged 18 years or older.
2. Healthy based on medical history, physical examination, and laboratory testing.
3. Able to provide informed consent.
4. Willing and able to complete all study procedures.
5. Have been screened for TSPO genotype under 01-M-0254 “The Evaluation of Patients 
with Mood and Anxiety Disorders and Healthy Participants”.
6.  Have their radial artery pulse checked for the presence of adequate ulnar collateral flow 
and the absence of any metal or foreign objects in both wrists*.
7. Agree to adhere to the lifestyle considerations (see Section 5.4)
*Does not apply to Phase 1 and 3 participants as they will not have an arterial line.


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5.2
EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation in this 
study:
1. Clinically significant abnormalities on EKG or laboratory testing. This includes CBC; 
acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen); hepatic panel 
(alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct); mineral panel 
(albumin, calcium, magnesium, phosphorus); prothrombin and partial prothrombin tests.
2. Participants should not have taken NSAIDs or willow bark tea for two weeks prior to the 
PET scan.
3. Any current Axis I diagnosis. 
4. Positive test for HIV.
5. Unable to have an MRI scan*.
6. History of neurologic illness or injury with the potential to affect study data 
interpretation.
7. History of seizures, other than in childhood and related to fever. 
8. Recent exposure to radiation (i.e., PET from other research) which when combined with 
this study would be above the allowable limits.
9. Inability to lie flat on camera bed for at least two hours, including claustrophobia and 
weight greater than the maximum for the scanner (500 lbs).
10. Pregnancy or breast feeding.
11. Able to get pregnant but does not use birth control.
12. 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. 
13. Unable to travel to NIH.
14. NIMH staff or an NIH employee who is a subordinate/relative/co-worker of the 
investigators.
*Phase 1 and 3 participants will not get an MRI.
5.2.1
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.
5.2.2
Exclusion of Pregnant or Breastfeeding Women
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.
5.2.3
Exclusion of Participants who are HIV Positive
Persons with HIV infection are excluded because HIV infection itself may change cAMP 
signaling.


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5.3
INCLUSION OF VULNERABLE PARTICIPANTS
5.3.1
Participation of NIH Staff or family members of study team members
NIH staff may be enrolled in this study as the population meets the study entry criteria and 
NIH Policy 404 will be followed.  There will be no direct solicitation of NIH employees, nor will 
they be directly recruited by or through their supervisors or co-workers to participate in this 
study.  Neither participation nor refusal to participate as a subject in the research will have an 
effect, either beneficial or adverse, on the participant’s employment or position at NIH. NIH 
employees must have permission from their supervisor and/or take leave in order to receive 
compensation if participation is during work hours.  Prior to enrollment, the NIH employee will 
be requested to review the Annual Leave Policy for NIH Employees.  Participant confidentiality 
and privacy will strictly be held in trust by the participating investigators, their staff, and the 
sponsor(s). 
Per NIMH Policy, NIMH employees, staff and their immediate family members will be 
excluded from the study due to ethical concerns about confidentiality and conflict of interest.  A 
copy of the ““NIH Frequently Asked Questions (FAQs) for Staff Who are Considering 
Participation in NIH Research” will be made available for NIH employees who wish to 
participate in this study.
5.4
LIFESTYLE CONSIDERATIONS
During this study, participants are asked to:

Abstain from strenuous exercise and from lifting more than 10 pounds using the affected 
arm for 48 hours after removal of the arterial line.

Abstain from taking NSAID pain medication for 2 weeks prior to the PET scan visit(s). If 
subject is experiencing pain, they can take Tylenol and still be eligible for the study.
5.5
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently assigned to the study intervention or entered in the study. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
5.6
STRATEGIES FOR RECRUITMENT AND RETENTION
Healthy volunteers will be recruited from protocol # 01M0254.
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 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: 


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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.  
Brochures and other IRB-approved recruitment materials or study information may be 
given directly to individuals interested in our research in both hard copy and electronic formats, 
depending on request. Associate Investigators and members of the NIMH Marketing & 
Community Relations Unit will distribute recruitment materials to individuals/groups, such as 
mental health clinics, hospitals, self-help and advocacy groups, and local clinicians. Clinicians 
who are contacted will be provided with information to disseminate to patients as they see fit. 
We will explain to them that individuals interested in participating in our studies will need to 
initiate contact with our group and that we will not make this initial contact.
The protocol and contact information to obtain further details will be listed on 
www.clinicaltrials.gov.
5.6.1
Costs
We expect participants to incur no costs for participating in this study.
5.6.2
Compensation
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 complete whether or not they opt for early 
withdrawal from participation. Without incomplete study procedures or unanticipated 
inconvenience, the total possible compensation for procedures is $220 for Phases 1 and 3, $390 
for Phase 2, and $650 for Phase 4. These compensation amounts do not account for time spent at 
the NIH, for which the first hour of each visit is compensated $20 and every subsequent hour is 
compensated $10. Payment will be submitted after completion of each visit to NIH through 
direct deposit. If the investigators need to delay study procedures or if additional time is need for 
completion, participants may receive additional compensation in accordance with NIH 
guidelines.  
Due to last-minute cancellations, appointments may be scheduled within 72 hours’ 
notice. Participants who are scheduled for appointments on short notice may be eligible for a 
bonus payment of $250 if they are scheduled and complete a visit with less than 72 hours’ notice.
Outpatient participants will receive support for travel, meals, and lodging according to 
NIH travel policy guidelines. Lodging may be provided directly or reimbursed according to 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.
Subjects undergoing Dosimetry Whole-body Scan (Phases 1 and 3)
Visit 1 to NIH
Screening
$20
Pregnancy test
$10
Visit 2 to NIH
PET scanning
$150


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Subjects undergoing Brain Scan (Phase 2)
Visit 1 to NIH
Screening
$20
Pregnancy test
$10
Visit 2 to NIH
PET scanning
$150
Arterial catheter
$60
Antecubital venous catheters
$30
Pregnancy test
$10
Movement restriction
$10
Visit 3 to NIH
   Brain MRI
$100
   Pregnancy test
$10
Total
$400*
Subjects undergoing Test-Retest Brain Scans (Phase 4)
Visit 1 to NIH
Screening
$20
Pregnancy test
$10
Visit 2 to NIH
PET scanning
$150
Arterial catheter
$60
Antecubital venous catheters
$30
Pregnancy test
$10
Movement restriction
$10
Visit 3 to NIH
PET scanning
$150
Arterial catheter
$60
Antecubital venous catheters
$30
Pregnancy test
$10
Movement restriction
$10
Visit 4 to NIH
   Brain MRI
$100
   Pregnancy Test
$10
Total
$660*
* Participants are eligible for a $250 bonus payment if they were scheduled and completed a PET 
visit within 72 hours’ notice.
Antecubital venous catheters
$30
Pregnancy test
$10
Movement restriction
$10
Total
$230*


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6
STUDY INTERVENTION
6.1
STUDY INTERVENTIONS(S) ADMINISTRATION
6.1.1
Study Intervention Description
Each participant will receive an injection of [18F]SF12051 during each PET scan.
6.1.2
Dosing and Administration
Each participant will be intravenously injected with about 5 mCi of [18F]SF12051 for each PET 
scan. The yield of the radioligand synthesis varies such that the available dose may be < 5 mCi. 
By prior agreement with NIH’s Radiation Safety Committee, the clinician covering the scan can 
approve a dose as low as half of the prescribed dose. We expect that a dose of 2.5-5 mCi will 
likely be adequate for all participants. The maximal dose will provide the best accuracy to 
measure radioactivity in brain with PET and the parent radioligand in plasma with radioHPLC.
6.1.2.1 Dose Escalation
None.
6.1.2.2 Dose Limiting Toxicity
As described in Section 2.3.1, toxicity from this radiolabeled drug comes from 
radioactive emissions and the mass dose of the nonradioactive carrier. Both the injected 
radioactivity and mass dose are many-fold lower than that required to cause toxicity.
6.1.2.3 Dose Modifications
The dose will not be modified by toxicity. Instead, the dose may be less than that 
prescribed, based on the PI’s judgment of the magnitude of noise that will be acceptable in the 
brain and blood measurements.
6.1.2.4 Drug Administration
The radioligand will be injected intravenously and must be administered within four 
hours of its preparation.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
The radioligands are prepared by the NIMH radiochemistry laboratory and handled by the 
PET department radiopharmacy according to the associated INDs and SOPs. The radioligands 
have minimal storage because they must be injected within one hour of their preparation.
6.2.1
Acquisition and Accountability
The radioligand will be delivered by the NIMH radiochemistry laboratory to the PET 
Department’s radiopharmacy. Acquisition and accountability are the responsibility of the NIMH 
radiochemistry laboratory.


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6.2.2
Formulation, Appearance, Packaging, and Labeling
Each product will be formulated in sterile, apyrogenic saline containing 10% dehydrated 
alcohol in a single-use vial and labeled according to requirements for PET drug products 
described in USP Chapter <823>. The following label will be affixed directly to the vials prior to 
filling:
Two additional labels are placed on the outer lead shielding used to transport the vial to 
the radiopharmacy:
 
6.2.3
Product Storage and Stability
Products are stable at controlled room temperature for the four-hour expiration period and 
have no additional storage requirements. Product vials are expected to be single-use, but if the 
seal is broken and additional product must later be withdrawn, the same storage conditions and 
original expiration time would apply.
6.2.4
Preparation
Products are provided as sterile, directly injectable solution in a multi-dose vial. The PET 
radiopharmacist will aseptically remove from the multi-dose vial only the volume required for a 
participant dose. If necessary, this volume will be diluted with 0.9% normal saline, USP to 12 
mL.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
This study is neither randomized nor blinded.
6.4
STUDY INTERVENTION COMPLIANCE
The injected dose is documented in CRIS.
6.5
CONCOMITANT THERAPY
This study has no concomitant therapies.


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7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1
DISCONTINUATION OF STUDY INTERVENTION
Discontinuation instituted by the investigator has been rare in our PET studies but would 
likely occur during one of the scans (i.e., MRI, two PETs). Examples include a participant 
experiencing such anxiety that the investigator recommends study discontinuation, even though 
the participant is willing to proceed, or a post-scan safety measurement that indicates a clinically 
significant abnormality that must be investigated and rectified before they can proceed. 
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue or withdraw a participant from the study for the 
following reasons:

A clinically significant AE, laboratory abnormality, or other medical condition or 
situation suggesting that continued participation in the study would not be in the best 
interest of the participant.

Screen failure, including positive pregnancy test.

Investigator discretion – e.g., excessive anxiety of the participant.
Any new clinically relevant finding will be reported as an AE, and the cause of 
discontinuation will be recorded in CRIS. In the event of any discontinuation, we will seek to 
obtain the next safety measure – i.e., post-scan safety labs or EKG.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons:

Significant study intervention non-compliance 

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Subject has completed the study follow-up period

Death

Screen Failure
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if they fail to return for a scheduled visit and is 
unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit as soon as 
practicable and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study.


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
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 

Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
SCREENING PROCEDURES
8.1.1
Screening activities performed prior to obtaining performed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:

Email, written, in person, or telephone communications with prospective subjects

Review of existing medical records to include H&P, laboratory studies, etc.

Review of existing MRI, x-ray, or CT images
8.1.2
Screening activities performed after a consent for screening has been signed
Prior to consenting to this study, participants will have undergone an initial blood sample 
to determine TSPO genotype under protocol 01M0254 “The Evaluation of Participants with 
Mood and Anxiety Disorders and Healthy Volunteers”, which allows for the sharing of collected 
data.
With the first visit under this protocol, all subjects will have a physical exam, EKG, and blood 
labs: CBC; acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen); hepatic panel 
(alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct); mineral panel (albumin, 
calcium, magnesium, phosphorus); prothrombin and partial prothrombin tests. Screening results 
will be reviewed by a clinically credentialed investigator before the subject undergoes any 
specific study procedures. Results of these tests will identify participants who should be 
excluded because of active medical problems or make participation in the protocol unsafe.
Subjects who successfully screen and are found eligible will be asked about their 
availability for scheduling of the PET scan(s) appointment.  Occasionally, we have a last-minute 
cancelation due to scheduling conflicts, COVID exposure, etc.  Given the complexities of 
arranging for the PET scan slot and synthesis of the ligand, we will inquire whether candidates 
have flexibility in their schedules to allow them to participate with less than 72 hours’ notice.  
We will maintain a list of those who agree to be available on short notice so that we may contact 
them if we have a scheduled subject that needs to cancel.  In the event that we schedule a 
participant with a72-hour notice, we will provide an additional payment of $250 if they come in 
and complete the PET scan.  
8.2
STUDY EVALUATIONS & PROCEDURES
In addition to the screening procedures described in Section 8.1, all participants will 
undergo:

Brain MRI (phase 2 and 4 only)  A brain MRI will be obtained for anatomic 
localization and will be performed on a 3 Tesla scanner located at the NIH Clinical 


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Center (Bethesda, Maryland). The MRI will take about one hour. Participants will 
undergo safety screening prior to the MRI to rule out contraindications such as 
cardiac pacemaker. If a suitable MRI is already available under another protocol or 
for clinical reasons, it will not be repeated if performed within one year.

Pregnancy Tests. For women of childbearing potential, urine pregnancy testing will 
be done within the 24 hours prior to any MRI or PET scan. If the pregnancy test is 
positive, PET and MRI will not be done, and the participant will be removed from the 
protocol.
8.2.1
PET Procedures
Radioligand
[18F]SF12051 will be administered via an indwelling intravenous catheter over ~1 
minute, within four hours after synthesis of the radioligand. The radioligands is stable during this 
period. 
Insertion of the intravenous line
An intravenous line will be placed in the arm. The venous line will be used to inject the 
radioligand and will be removed at the end of the day. The IV line may be replaced if it fails to 
remain patent.
PET acquisition for brain and/or lung imaging
PET scans will be performed using a PET/CT or the HRRT. The choice of the scanner for 
a particular study will depend on scanner availability. Participants will be placed on the scanner 
bed with their head held firmly in place with a thermoplastic mask or a head holder fixed to the 
bed. A transmission scan will be performed before the PET scan to measure and correct for 
attenuation. Tracer infusions will be performed in the nuclear medicine department, while the 
subject is on the scanner bed.
After an intravenous bolus of about 5 mCi, arterial blood samples will be drawn from the 
arterial catheter during the PET scan. We will collect about 20-25 arterial samples. First, blood 
samples will be drawn every 15 seconds after injection for about 3 to 5 minutes, and then they 
will be collected every 5, 10, 15, or 30 minutes. The total amount of arterial blood will be about 
100 mL. PET images of the brain will be acquired in three-dimensional mode with increased 
length of frame for a total of 120 minutes. The duration may be shortened on the basis of the 
results of time stability analysis.
At the end of the scans, the arterial and venous lines will be removed, and the subject will 
be instructed to void frequently to minimize radiation exposure.
PET acquisition for dosimetry 
Whole body dosimetry scans will be performed with a PET/CT. The choice of the 
scanner for a particular study will depend on scanner availability. No arterial sampling will be 
done for dosimetry studies. Both a pre-injection transmission scan and a series of dynamic 
emission scans will be acquired. Each subject will be imaged in contiguous segments from the 
top of the head to a point below the gonads. To minimize extraneous motion, all subjects may 
wear a head-holding mask and will have their arms and abdomen wrapped with body-restraining 
sheets. This may add some additional discomfort. Venous samples up to 30 mL may be obtained 


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to measure [18F]SF12051 levels. Before injection of the radioligand, a transmission scan will be 
acquired for subsequent attenuation correction. Then, an initial set of dynamic emission scans 
will be acquired following the intravenous injection of [18F]SF12051. The acquisition of each 
cycle will begin with an emission scan at the first bed position (i.e., the head), and continue by 
moving the bed distally to the next body segment. Then, a second transmission scan, identical to 
the first, will be performed followed by a second set of dynamic emission scans.
Arterial Line Placement
For brain scans, a radial artery catheter will be inserted by the NIH Clinical Center 
Anesthesiology Department, after the presence of adequate ulnar collateral flow has been 
established.   The skin at the site of the puncture will be anesthetized with 1% lidocaine. The 
catheter will be perfused (3 mL/h) with heparin solution (600 units/L) during the procedure. The 
amount of heparin infused will be much smaller than the amount necessary to produce any 
systemic anticoagulant effect.
8.2.2
Biospecimen Evaluations
After injections of the radioligand during brain scans, arterial sampling will be performed 
continuously at early time points and discretely at later time points, but this plan can be modified 
if required to improve quality of data. The arterial blood samples will be processed for total 
radioactivity though a gamma counter and will processed through high performance liquid 
chromatography (HPLC) to measure metabolites. Correlation between arterial radioactivity and 
brain activity via the PET scan will allow for pharmacokinetic modeling and accurate 
quantification of the signal.
8.2.3
Correlative Studies for Research/Pharmacokinetic Studies
See Section Error! Reference source not found..
8.2.4
Samples for Genetic/Genomic Analysis
Blood for TSPO screening will be acquired only under protocol 01M0254.
8.2.4.1 Management of Results
Participants will have access to “clinical” medical results via the patient portal (e.g., 
laboratory tests, EKG, and MRI). In addition, we will notify them if any of these results are 
abnormal. They will not have access to investigational results from the PET scan, as they have 
no normal ranges.
8.2.4.2 Genetic counseling
None.
8.3
SAFETY AND OTHER ASSESSMENTS
Safety Monitoring of PET Scans
Data for safety monitoring will be recorded at three timepoints: no more than three hours 
before injection, about the middle of the PET scan, and after the PET scan. Recorded data 
include: blood pressure, pulse, respiratory rate, and EKG (either 3- or 12-lead). The following 
laboratory tests will also be obtained, but only at two timepoints (before and after the PET scan: 
CBC, acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen), hepatic panel 


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(alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct), mineral panel (albumin, 
calcium, magnesium, phosphorus).
Pregnancy Tests
For women of childbearing potential, urine pregnancy testing will be done within the 24 
hours prior to any MRI or PET scan. If the pregnancy test is positive, PET and MRI will not be 
done, and the participant will be removed from the protocol.
Follow-up Procedures 
Participants will be contacted one to three days after each PET scan to determine whether 
they have had any untoward sequelae.
8.4
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
8.4.1
Definition of Adverse Event
Adverse Event (AE) means any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
8.4.2
Definition of Serious Adverse Events (SAE)
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes: death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
8.4.3
Classification of an Adverse Event
8.4.3.1 Severity of Event
For adverse events (AEs) not included in the protocol defined grading system, the 
following guidelines will be used to describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.]


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8.4.3.2 Relationship to Study Intervention
All adverse events (AEs) must have their relationship to study intervention assessed by 
the investigator who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
•
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition.
•
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments).
•
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.]
8.4.3.3 Expectedness 
The PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention.
8.4.4
Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to 
the attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor.


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All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode.
Credentialed clinicians will record all reportable events with start dates occurring any 
time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after 
the last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information 
until resolution or stabilization.
8.4.5
Adverse Event Reporting 
Non-SAEs will be reported to the ISM (annually), to the IRB at the time of Continuing 
Review and to the Sponsor at regular intervals per request.
8.4.6
Serious Adverse Event Reporting 
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*
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.
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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. MRNs 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.
8.4.7
NIH Intramural IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of an unanticipated problem or is new 
information that might affect the willingness of subjects on the NIH study to enroll or remain in 
the study will need to be reported to the NIH Intramural IRB.
8.4.8
Events of Special Interest 
None.
8.4.9
Reporting of Pregnancy 
Participants will be excluded if they are or may become pregnant.
8.5
UNANTICIPATED PROBLEMS
8.5.1
Definition of Unanticipated Problems (UP)
Any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and
•
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and
•
Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected.


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8.5.2
 Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the NIH Institutional 
Review Board (IRB) as per Policy 801.
9
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESIS
Primary Endpoint(s): We hypothesize that [18F]SF12051 will show strong binding 
affinity for TSPO regardless of genotype.
Secondary Endpoint(s): We hypothesize that the retest variability and reliability of 
[18F]SF12051 will allow its use in clinical protocols.
We hypothesize that the dosimetry and biodistribution of [18F]SF12051 will be similar to that of 
other 18F tracers.
9.2
SAMPLE SIZE DETERMINATION
To evaluate genotype sensitivity of [18F]SF12051 we calculated the percent difference in 
binding values necessary to differentiate between HABs, MABs and LABs. This was based on 
our previous results with [11C]ER176 in healthy volunteers of different genotypes (Ikawa et al 
2016). The mean VT of HH subjects (HABs; n = 9) for whole brain was 4.5 mL/cm3 with a 
standard deviation of 1.4 mL/cm3. In addition, the VT of HH subjects was 40% higher than the VT 
of HL subjects. Assuming the same SD for [11C]ER176 and [18F]SF12051, we can calculate how 
much of a difference in mean VT can be detected between genotypes. Power analysis based on VT 
of HH subjects from [11C]PBR28 scans showed that with a sample size of 10 for each binder 
group, a power of 80% and alpha of 0.05 the percent difference to be detected from the mean 
value of a HAB is 40%. That is, the difference in mean VT between HH and other genotypes 
should be >40% for it reach a statistical significance with a sample size of 10. Therefore, we 
require a recruitment of 34 in total for HABs, MABs and LABs under Phase 2 and 4 considering 
some withdrawals.
We wish to balance the number of subjects in the three TSPO genotypes: HAB, MAB, 
and LAB. Although all genotypes will be accepted during the initial scans, we will likely require 
specific genotypes toward the end of the scan, especially for the rare LABs. For this reason, we 
may select individuals based on TSPO genotype in order to have roughly equal number of 
subjects in the three groups.
9.3
POPULATIONS FOR ANALYSES
All subjects are healthy volunteers.
9.3.1
Evaluable for toxicity 
No toxicity is expected from the radioligand; nevertheless, safety will be monitored as 
described in Section 8.3.
9.3.2
Evaluable for objective response 
No therapeutic response is expected from the radioligand as we are testing a diagnostic 
agent at sub-pharmacological doses.


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9.3.3
Evaluable Non-Target Disease Response
Not Applicable. 
9.4
STATISTICAL ANALYSES
9.4.1
General Approach
Brain imaging data will be analyzed with kinetic modeling. PET and MRI scans will be 
coregistered for anatomic definition of regions of interest. SUV will be calculated in various 
brain regions. Parametric images will be created using PMOD software (PMOD Technologies 
Ltd., Zurich, Switzerland). The kinetic modeling will give us the [18F]SF12051 binding values, 
and their identifiability and stability over time. 
In whole body imaging studies, organ time-activity curves will be obtained from the 
dynamic PET images and used to calculate organ residence times. Residence time of the urinary 
bladder may be calculated using a dynamic bladder model (12). The residence times will be used 
in OLINDA/EXM (http://www.doseinfo-radar.com/OLINDA.html) to obtain radiation-absorbed 
dose estimates. 
To consider inter-subject variability, radiation absorbed doses are usually estimated from 
approximately 6-8 subjects (13-15). To also take into account possible gender differences, we 
propose to study approximately an equal number of male and female subjects in the whole-body 
imaging study. In addition, we plan at least 3 subjects for each binder group (9 subjects in total). 
Considering the requirement of one subject for the initial Phase 1 and any possible withdrawals, 
we seek a total of 10 subjects for Phase 3.
9.4.2
Analysis of the Primary Endpoints
The outcome measure for the primary endpoint will be the total distribution volume and 
summarized as mean ± SD.
9.4.3
Analysis of the Secondary Endpoint(s)
The outcome measure for secondary endpoints will be the total distribution volume and 
the absorbed dose. Retest variability will be assessed as absolute variability and reliability will 
be assessed as interclass correlation coefficient (ICC). Dosimetry will be measured as absorbed 
dose and summarized as mean ± SD for organs.
9.4.4
Safety Analyses
The safety measures will be recorded but not analyzed statistically.
9.4.5
Baseline Descriptive Statistics
Mean +/- SD for age, weight, etc.
9.4.6
Planned Interim Analyses
None.
9.4.7
Sub-Group Analyses
The different genotype groups will be analyzed separately.


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9.4.7.1 Tabulation of individual Participant Data
Individual participant data will be listed by measure and timepoint. 
9.4.8
Exploratory Analyses
None.
10 REGULATORY AND OPERATIONAL CONSIDERATIONS
10.1
INFORMED CONSENT PROCESS
10.1.1 Consent/Assent Procedures and Documentation
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”. 
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 
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 signed consent form will 
be given will be placed in the medical record, to the participant and also uploaded in CRIS. .  


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10.1.2 Consent for minors when they reach the age of majority 
Not applicable.
10.1.3 Considerations for Consent of NIH staff, or family members of study team members
Consent for NIH employees will be obtained as described in Section 5.3.1.
10.1.4 Consent of Subjects who are, or become, decisionally impaired
Adults unable to provide consent are excluded from enrolling in the protocol. For those
subjects that become incapacitated, they will be removed from the study. 
10.2
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).
10.3
CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the NIH for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
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To further protect the privacy of study participants, a Certificate of Confidentiality has 
been issued by the National Institutes of Health (NIH).  This certificate protects identifiable 
research information from forced disclosure. It allows the investigator and others who have 
access to research records to refuse to disclose identifying information on research participation 
in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, 
state, or local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
10.4
FUTURE USE OF STORED SPECIMENS AND DATA
In the consent form, we ask permission of the participant (yes/no response) to share 
imaging and other research data during or after completion of the study with collaborating 
laboratories at the NIH or outside of the NIH and/or submitted to open-access repositories for 
secondary research that may or may not involve a collaboration with the NIMH. Such open 
access repositories (e.g., OpenNeuro, sponsored by the NIMH) allows anyone to access the data 
for any purpose. Data will be stripped of all identifiers, including name, address, contact 
information, and medical record number prior to sharing. In addition, the face will be removed 
from MRI images. The data may be coded, but the key to the code will not be provided to any 
collaborator or party external to the NIH. After the study is completed, the de-identified data and 
the code may be indefinitely maintained at the NIH and used for secondary analyses. In contrast 
to data, no biological samples will be shared.
10.5
SAFETY OVERSIGHT
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial complies with the currently approved protocol/amendment(s), with 
International Conference on Harmonization Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
Monitoring for this study will be performed by an independent safety monitor (ISM), 
William Regenold, M.D.C.M, who is a board-certified  psychiatrist with full clinical privileges at 
the NIH Clinical Center.  
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 reviews.
10.6
CLINICAL MONITORING
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 


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(subjects' charts, laboratory analyses and test results, 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.
10.7
QUALITY ASSURANCE AND QUALITY CONTROL
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.
10.8
DATA HANDLING AND RECORD KEEPING
10.8.1 Data Collection and Management Responsibilities
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the Principal Investigator (PI). The PI is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study.  Data recorded in the 
electronic case report form (eCRF) derived from source documents should be consistent with the 
data recorded on the source documents. 
Clinical data (including AEs, eligibility, and primary outcome data) will be entered into 
the Clinical Trials Database (CTDB) at NIH. CTDB complies with the Federal Information 
Security Management Act of 2002 and 21 CFR Part 11. The data system includes audit trail, 
password protection, and control staff access level to the application and data. Edit checks 
implemented at the eCRF include: data type validation and numeric range checks. Clinical data 
will be entered directly from the source documents.


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10.8.2 Study Records Retention
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonization (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention, or as per the NIH Intramural Records Retention Schedule. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained.
10.9
PROTOCOL DEVIATIONS AND NON-COMPLIANCE
It is the responsibility of the PI to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH Institutional Review Board as per Policy 801.  All 
deviations must be addressed in study source documents, reported to the NIMH Program Official 
and the IND sponsor; Dr. Maryland Pao, Clinical Director, holds both of these positions.  The 
investigator is responsible for knowing and adhering to the reviewing IRB requirements.
10.9.1 NIH Definition of Protocol Deviation
A protocol deviation is any changed, divergence, or departure from the IRB-approved 
research protocol. 

Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare, or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study.

Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study.
10.10 PUBLICATION AND DATA SHARING POLICY
10.10.1
 Human Data Sharing Plan
This study will be conducted in accordance with the following publication and data 
sharing policies and regulations:
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication.
This study will comply with the NIH Data Sharing Policy and Policy on the 
Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and 
Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, 
and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  
10.10.2
 Genomic Data Sharing Compliance
The only genomic data analyzed will be TSPO binding affinity, which will be shared 
under the conditions set in 10.10.1.


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10.11 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the NIMH has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.


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Version Date: 12/05/23
11 ABBREVIATIONS
AE
Adverse Event
CFR
Code of Federal Regulations
COC
Certificate of Confidentiality
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DCC
Data Coordinating Center
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
HABs
High-affinity Binders
ICH
International Conference on Harmonization 
IND
Investigational New Drug 
IRB
Institutional Review Board
ISM
Independent Safety Monitor
LABs
Low-affinity Binders
MABs
Medium-affinity Binders
MRI
Magnetic Resonance Imaging
NCT
National Clinical Trial
NIH 
National Institutes of Health
NIH IC
NIH Institute or Center
PET
Positron Emission Tomography
PI
Principal Investigator
SAE
Serious Adverse Event
SNP
Single Nucleotide Polymorphism
SOA
Schedule of Activities
SOP
Standard Operating Procedure
SUV
Standardized Uptake Value
TSPO
18-kDa Translocator Protein
UP
Unanticipated Problem
US
United States
VT
Total (specific plus non-displaceable) distribution volume


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