Evaluation of Monosodium Glutamate (MSG) to Reduce Salivary Gland and Renal Accumulation of PSMA-binding Radiopharmaceuticals
Phase: NA
Conditions: Prostate Cancer, Prostate Cancer Metastatic, Prostatic Neoplasm
Sponsor: British Columbia Cancer Agency

 
 
Evaluation of monosodium glutamate (MSG) to 
reduce salivary gland and renal accumulation of 
PSMA-binding radiopharmaceuticals 
A sub-study of REB protocol H16-01551 ([18F]-DCFPyL Positron Emission Tomography / Computed 
Tomography (PET/CT) for Assessment of Recurrent Prostate Cancer”)  
  
 
RESEARCH ETHICS BOARD PROTOCOL NUMBER: H18-02227   
 
Principal Investigator:  
François Bénard, MD 
Co-Investigators:  
 
Don Wilson, MD  
 
 
 
 
 
VERSION 1.0 – OCTOBER 12, 2018 
FUNCTIONAL IMAGING DEPARTMENT 
BC CANCER - VANCOUVER  
 

Sponsor Signature Page 
 
 
 
François Bénard, MD 
 
 
 
 
 
 
Date 
Sponsor (Lead Study Investigator) 
 
 
 
 
 
 
 
 
 
 
 
Short Title: MSG in PSMA imaging 
 
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Protocol Signature Page 
 
 
 
Principal Investigator 
(Print Name) 
 
 
 
 
 
 
 
 
Principal Investigator 
(Signature)   
 
 
 
Date 
 
 
 
The above signed confirms herewith to have read and understood this study 
protocol, and furthermore, to accomplish this study according to the Protocol 
and the Good Clinical Practice guidelines, as well as local regulations, and to 
accept respective revisions conducted by authorized representatives 
 
 
 
 
 
 
 
 
 
 
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Table of Contents 
Table of Contents ....................................................................................................................... 4 
1. 
List of Abbreviations ....................................................................................................... 8 
2. 
Protocol Synopsis ........................................................................................................... 9 
3. 
Background Information ................................................................................................10 
3.1. 
PSMA PET/CT imaging .........................................................................................10 
3.2. 
Radioligand therapy of prostate cancer ..................................................................10 
3.3. 
Pharmacological approaches for salivary gland and renal protection .....................11 
3.4. 
Monosodium glutamate to block non-specific accumulation of PSMA ligands ........12 
3.5. 
The safety of monosodium glutamate, a flavour-enhancing ingredient ...................12 
3.6. 
Investigational Product ...........................................................................................13 
3.7. 
18F-DCFPyL ...........................................................................................................14 
4. 
Rationale for Study ........................................................................................................14 
5. 
Risks and Benefits .........................................................................................................14 
5.1. 
Radiation exposure ................................................................................................14 
5.2. 
Oral MSG administration ........................................................................................15 
6. 
Mode of Administration and Dose ..................................................................................15 
7. 
GCP and Regulatory Compliance ..................................................................................15 
8. 
Target Population ..........................................................................................................15 
9. 
Trial Objective and Purpose ..........................................................................................15 
9.1. 
Hypothesis .............................................................................................................16 
10. 
Trial Design ...............................................................................................................16 
10.1. 
Endpoints...............................................................................................................16 
Study Design .....................................................................................................................16 
10.2. 
Screening and Enrollment ......................................................................................16 
10.3. 
Obtaining Informed Consent ..................................................................................16 
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10.4. 
Assignment of Participant Identification Numbers ..................................................17 
10.5. 
Schematic Flow Diagram .......................................................................................18 
10.6. 
Measure to Minimize/Avoid Bias ............................................................................18 
10.7. 
Trial Procedures ....................................................................................................19 
10.8. 
Study Duration and Follow-up Visits ......................................................................20 
11. 
Accountability Procedures for the Investigational Product ..........................................21 
12. 
Trial Treatment Randomization Codes and Procedures for Breaking Codes .............21 
13. 
Data ...........................................................................................................................22 
14. 
Selection and Withdrawal of Participants ...................................................................22 
14.1. 
Record of Study Participants ..................................................................................22 
14.2. 
Participant Inclusion Criteria ..................................................................................22 
14.3. 
Participant Exclusion Criteria .................................................................................22 
14.4. 
Participant Withdrawal ...........................................................................................23 
15. 
Treatment of Participants ...........................................................................................23 
16. 
Study Materials ..........................................................................................................23 
16.1. 
Authorized Suppliers ..............................................................................................24 
16.2. 
Preparation ............................................................................................................24 
16.3. 
Packaging and Labelling ........................................................................................24 
16.4. 
Storage and Disposition of Study Agent .................................................................25 
17. 
Assessment of Efficacy ..............................................................................................25 
17.1. 
Efficacy Parameters ...............................................................................................25 
17.2. 
Methods for Assessing and Analyzing Efficacy ......................................................25 
18. 
Assessment of Safety ................................................................................................25 
18.1. 
Specification of Safety Parameters .......................... Error! Bookmark not defined. 
18.2. 
Methods for Analyzing and Assessing Safety ........................................................25 
18.3. 
Adverse Event Reporting .......................................................................................26 
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18.4. 
Site Responsibilities ...............................................................................................26 
18.5. 
Definition of Adverse Event ....................................................................................26 
18.6. 
Definition of Serious Adverse Event .......................................................................26 
18.7. 
Adverse Event Attribution ......................................................................................27 
18.8. 
Expected Adverse Events from PET/CT scan ........................................................28 
18.9. 
Adverse Event Follow-up after 18F-DCFPyL ...........................................................28 
18.10. 
Type and Duration of Follow-up of Participants after Adverse Events ................29 
19. 
Statistics ....................................................................................................................29 
19.1. 
Description of statistical methods ...........................................................................29 
19.2. 
Sample Size Considerations ..................................................................................30 
19.3. 
Criteria for the Termination of the Trial ...................................................................31 
19.4. 
Accounting for Missing, Unused and Spurious Data ..............................................31 
19.5. 
Procedures for Reporting Protocol Deviations .......................................................31 
19.6. 
Selection of Participants to be Included in the Analyses ........................................31 
20. 
Direct Access to Source Data/ Documents ................................................................31 
21. 
Quality Control and Quality Assurance ........................ Error! Bookmark not defined. 
22. 
Data Management .....................................................................................................32 
22.1. 
Data Handling and Record Keeping ......................... Error! Bookmark not defined. 
22.2. 
Case Report Forms (CRF), Source Documents and Source DataError! Bookmark 
not defined. 
22.3. 
Source Data Verification .......................................... Error! Bookmark not defined. 
22.4. 
Data Management ................................................... Error! Bookmark not defined. 
23. 
Ethical Considerations ...............................................................................................32 
23.1. 
Consent ................................................................... Error! Bookmark not defined. 
23.2. 
REB Review ............................................................ Error! Bookmark not defined. 
24. 
Regulatory Requirements and Investigator Obligations .............................................32 
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24.1. 
GCP and Investigator Compliance .........................................................................32 
24.2. 
Documentation and Record-Keeping .....................................................................32 
24.3. 
Premature Termination of the Study ......................................................................32 
24.4. 
Clinical Study Report / Publication .........................................................................32 
24.5. 
Compensation / Indemnification .............................................................................32 
24.6. 
Protocol Amendments............................................................................................33 
25. 
Financing and Insurance ...........................................................................................34 
26. 
Supplements .............................................................................................................34 
27. 
References ................................................................................................................34 
 
 
 
 
 
 
 
 
 
 
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1. List of Abbreviations 
 
 
 
ACRIN 
American College of Radiology Imaging Network 
AE 
Adverse Event 
225Ac 
Actinium-225 
BC 
British Columbia 
cm 
Centimeter 
CRF 
Case Report Form 
CRPC 
Castration resistant prostate cancer 
CT 
Computed Tomography 
CTA 
Clinical Trial Application 
ECOG 
Eastern Cooperative Oncology Group 
EuK 
Glutamate-urea-Lysine 
18F-DCFPyL 
2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-
pentanedioic acid 
18F 
Fluorine-18 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
%ID/g 
Percent injected dose per gram of tissue 
IV 
Intravenous 
177Lu 
Lutetium-177 
MBq 
Mega Becquerel 
mL 
Milliliter 
mm 
millimetre 
MRI 
Magnetic Resonance Imaging 
MSG 
Monosodium Glutamate 
mSv 
Millisievert 
ng/mL 
nanogram per milliliter 
PBS 
Phosphate-buffered saline 
PET 
Positron Emission Tomography 
PMPA 
(Phosphonomethyl) pentanedioic acid 
PSA 
Prostate Specific Antigen 
PSMA 
Prostate Specific Membrane Antigen 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SPECT 
Single Photon Emission Computed Tomography 
SUV 
Standardized uptake value 
w/v 
weight/volume 
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2. Protocol Synopsis 
STUDY OBJECTIVES 
Primary: 
 
 
 
 
Secondary: 
 
 
 
 
To evaluate the effects of orally administered monosodium 
glutamate (MSG) on salivary gland accumulation of [18F]-
DCFPyL. 
 
• To evaluate the effects of MSG on renal accumulation of [18F]-
DCFPyL. 
• To evaluate the effects of MSG on tumour accumulation of 
[18F]-DCFPyL. 
• To evaluate the tolerability and compliance with an orally 
administered solution of MSG 
 
STUDY DESIGN 
This is a prospective single blinded intra-participant study to 
evaluate the effects of orally administered MSG vs placebo 
on18F-DCFPyL PET/CT biodistribution.  
STUDY POPULATION 
 
Number of Participants: 
10 participants. 
Age: 
Age greater than or equal to 19 years  
Study specific 
requirements: 
Participants who are eligible to participate in protocol H16-
01551 entitled ‘[18F]-DCFPyL Positron Emission Tomography / 
Computed Tomography (PET/CT) for Assessment of Recurrent 
Prostate Cancer.’ 
INVESTIGATIONAL 
PRODUCT 
 
Product 
[18F]-DCFPyL 
Route of administration: 
Intravenous 
Dosage(s) and 
frequency: 
Radioactive dose of [18F]-DCFPyL: 296-521 MBq per injection 
Two injections per participant (two PET/CT scans) 
Duration of dosing: 
Single dose for each PET/CT scan 
EVALUATION 
CRITERIA 
 
Efficacy: 
Salivary gland and renal accumulation of [18F]-DCFPyL 
measured by the standardized uptake value. 
 
Safety: 
Vital signs before MSG administration, immediately before [18F]-
DCFPyL administration, 5-15 minutes following [18F]-DCFPyL 
administration, 1 and 2 hours after [18F]-DCFPyL administration; 
Adverse event collection. 
 
 
 
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3. Background Information 
3.1. 
PSMA PET/CT imaging 
The prostate-specific membrane antigen (PSMA) is a cell surface transmembrane glycoprotein 
that is significantly overexpressed in prostate cancers (1). It is also expressed in lower amounts 
in normal tissues such as the liver, gastrointestinal track and kidneys, as well as the vascular 
endothelium of some non-prostatic tumours (eg. breast, renal, lung) (2).   
Several inhibitors of PSMA have been developed over the years, with the aim of blocking the 
enzymatic function of this protein. PSMA has multiple names, including glutamate 
carboxypeptidase II (GCPII), folate hydrolase I (FOLH1), and N-acetyl-L-aspartyl-L-glutamate 
peptidase I (NAALADase).  
Due to high overexpression of PSMA in prostate cancer, there has been long term interest in 
targeting this protein to deliver radioisotopes to prostate cancer cells by using PSMA-binding 
molecules as a carrier. Most investigators have focused on the use of radiolabeled antibodies 
(notably the J591 antibody) or peptidomimetics derived from the glutamate-urea-lysine (EuK) 
sequence, to develop single positron emission computed tomography (SPECT) and positron 
emission tomography (PET) radiotracers.  
Many radiopharmaceuticals showing high sensitivity/specificity for PSMA-expressing tissues 
have been developed, and the use of PSMA imaging is rapidly growing worldwide (3). While 
there is extensive experience reported in retrospective studies with [68Ga]-HBED-PSMA-11 (4, 
5), new radiopharmaceuticals labeled with fluorine-18, such as [18F]-PSMA-1007(6) and [18F]-
DCFPyL (7-9) are rapidly gaining in popularity due to their advantages over 68Ga-labelled 
compounds. 
3.2. 
Radioligand therapy of prostate cancer  
PSMA radiopharmaceuticals derived from the EuK backbone are also showing promise as a 
treatment for castration-resistant metastatic prostate cancer (10-12). In this application, the 
diagnostic radioisotope is changed for a beta (177Lu) or alpha (225Ac) emitter which induces 
radiation damage to cancer cells that bind the radiotracer, as well as surrounding cells. With 
both radioisotopes, the activity administered to patients is limited by toxicity to normal organs. 
Due to high accumulation in the kidney and salivary glands (13), potential side effects include 
renal dysfunction and xerostomia (10-12). Marrow toxicity may also occur (14), but this effect is 
probably related to indirect exposure from bone metastases in patients with extensive osseous 
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involvement. Xerostomia is more cumbersome with alpha-emitters, causing patients to 
discontinue treatment (15).   
With radioligand therapy using 177Lu-PSMA-617, in an Australian phase II study (12), where 4 
cycles of treatment were administered, 87% of patients developed xerostomia. Most cases of 
xerostomia were mild (grade 1), and controlled with no treatment or salivary substitution gels. 
17% of patients experienced dry eyes with recovery over time.  
With 177Lu-PSMA-617, Delker et al. reported absorbed doses per cycle of 0.6 Gy/GBq, 
1.4 Gy/GBq, 0.1 Gy/GBq, 0.1 Gy/GBq and 0.012 Gy/GBq for the kidneys, salivary glands, 
liver, spleen and bone marrow, respectively (16). Kratochwil reported doses to the kidney of 
0.75 Gy/GBq, red marrow of 0.03 Gy/GBq, and salivary gland of 1.4 Gy/GBq (17). Yadav et 
al. measured 1.24 ± 0.26 and 0.99 ± 0.31 Gy/GBq, for the salivary glands and kidneys, with 
a mean absorbed doses to the liver, urinary bladder and red marrow were 0.36 ± 0.10, 
0.243 ± 0.09 and 0.048 ± 0.05 Gy/GBq, respectively (18). Kabasakal reported doses to the 
salivary glands, kidney and marrow at 1.17 ± 0.31 Gy/GBq 0.88 ± 0.40 Gy/GBq and 0.03 ± 
0.01 Gy/GBq respectively (19). 
Thus, the critical organs with EuK PSMA radiopharmaceuticals are the salivary gland and 
kidneys. The marrow is probably mainly affected when there is extensive metastatic 
infiltration of the bones. A means of decreasing radiation exposure to normal organs without 
affecting tumour uptake would allow administration of higher amounts of radioactivity with 
presumably greater anti-tumour effects. 
3.3. 
Pharmacological approaches for salivary gland and renal protection 
Different pharmaceuticals including 2-(phosphonomethyl)pentanedioic acid (PMPA), a PSMA 
inhibitor, have been explored for nephroprotection (20, 21). PMPA displaced renal activity of a 
PSMA radiotherapeutic in cancer models, but this was generally accompanied by a reduction in 
tumour uptake (20, 21). Mannitol infusion reduced renal uptake of 68Ga-PSMA-11 (22). Its 
effect on tumour uptake requires further investigations. Botulinum toxin administered in the 
parotid gland of a patient significantly decreased PSMA-ligand uptake (23). While this procedure 
is promising, it is invasive, costly, and may affect salivary gland function for weeks.   
While PSMA is expressed to low levels in salivary glands and kidneys, part of PSMA-ligand 
uptake in salivary glands may be due to off-target binding, as uptake is not observed in human 
studies with the radiolabeled J591 monoclonal antibody (24-26). RNA and protein expression is 
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relatively low in salivary glands according to the human protein atlas (27, 28), compared to the 
prostate gland, duodenum and kidneys, yet radiotracer accumulation is equivalent or higher. 
This led to the hypothesis that a large fraction of salivary gland accumulation of EuK ligands 
might be caused by mechanisms other than PSMA binding. As glutamate is one of the most 
potent stimulator of salivary flow (29), glutamate transporters and receptors (metabotropic 
glutamate receptors, umami taste receptor, others) are potential candidates to explain the non-
specific binding of EuK ligands to salivary glands.  
3.4. 
Monosodium glutamate to block non-specific accumulation of PSMA ligands 
As many PSMA ligands integrate glutamate for binding to PSMA, we hypothesized that 
monosodium glutamate (MSG) could reduce non-specific accumulation in non-cancerous 
tissues. MSG is a well-studied taste enhancer and a potent stimulator of salivary flow (29, 30). 
MSG was investigated to reduce uptake of 68Ga-PSMA-11 in salivary glands and kidneys, in 
LNCaP tumour-bearing mice (31). The mice were injected intraperitoneally with MSG (657, 329, 
or 164 mg/kg), or phosphate-buffered saline (PBS) as a negative control. Fifteen minutes later, 
the mice were intravenously administered 68Ga-PSMA-11 as a representative EuK radioligand. 
PET/CT imaging and biodistribution studies were performed one hour after radiotracer 
administration. Tumour uptake was not statistically different between groups: 657 mg/kg 
(8.42±1.40 %ID/g), 329 mg/kg (7.19±0.86), 164 mg/kg (8.20±2.44), PBS (8.67±1.97). Kidney 
uptake was significantly lower in the 657 mg/kg group (85.8±24.2 %ID/g) than in the 329 mg/kg 
(159±26.2), 164 mg/kg (211±27.4), and PBS groups (182±33.5); p < 0.001. Salivary gland 
uptake was lower in 657 mg/kg (3.72±2.12 %ID/g) and 329 mg/kg (5.74±0.62) groups compared 
with PBS group (10.04±2.52, with a p value less than 0.01). This study concluded MSG 
decreased salivary and kidney uptake of 68Ga-PSMA-11 in a dose-dependent manner, while no 
difference in tumour uptake was observed.  
Obviously, these represent large doses of MSG, and it is not known what doses are necessary 
to achieve similar effects in human participants. It is also not clear if the effects of MSG are 
related to saturation of low capacity PSMA binding sites, or due to blocking of [18F]-DCFPyL to 
other targets, as MSG has a Ki of 0.9 mM against human PSMA, measured in LnCAP cells. 
3.5. 
The safety of monosodium glutamate, a flavour-enhancing ingredient 
Although MSG has been linked to headaches and “Chinese restaurant syndrome” (32), 
numerous studies have shown MSG to be very safe, and the causal relationship with 
headaches has been questioned (33). Based on a no adverse event limit of 3,200 mg/kg/day for 
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neurodevelopmental toxicity, the European Food Safety Authority recommended an acceptable 
daily intake of 30 mg/kg/day (34, 35).  The LD50 for orally administered MSG in rats in mice is 
approximately 15-18 g/kg (equivalent to an oral dose of 1.05 – 1.26 kg in an average adult 
male) (36). The average daily intake of glutamate in food is 13 g per day (37). 
Glutamate was administered intravenously at a rate of 30-40 mg/kg/hour, to a maximum 
infusion of 9.2 g of a solution comprised of pH 6 solution of L-glutamic acid 9.2 g, NaCl 0.8 g, in 
500 mL of water, in a study on the benefits of glutamate infusion during cardiopulmonary bypass 
surgeries (38). Fernstrom administered a single oral dose of 12.7 g of MSG in humans without 
undesirable events, with return of plasma glutamate levels to baseline after 3 hours (39). 
Chevassus et al. administered 150 mg/kg orally to 18 healthy volunteers, with a 75g oral 
glucose load, to investigate the effects of glutamate on insulin secretion. One participant 
reported dizziness, gastric discomfort and nausea, while another reported headaches, all of 
which were resolved by the next day (40). Shimada administered doses of 150 mg/kg daily 
(approximately 12 g for an 80 kg man) to 32 healthy volunteers for 5 consecutive days. They 
noted an increase in systolic and diastolic blood pressure as well as headaches, but no effects 
on muscle sensitivity (41).  
The MSG quantity required to achieve effective off-target blocking of EuK radiolabeled 
derivatives in humans is not known, as human physiology may differ. We know from the 
evaluation of numerous EuK radiotracers in the preclinical setting, as well as the ongoing clinical 
trial 18F-DCFPyL, that salivary gland accumulation of EuK radiotracer is significantly lower in 
mice compared to humans. There are also interspecies difference in umami (glutamate) taste 
sensitivity. For example, the mouse umami receptor (mT1R1/mT1R3) is significantly less 
responsive to glutamate than the human (hT1R1/hT1R3) counterpart (42). 
3.6. 
Investigational Product 
18F-DCFPyL is a sterile, non-pyrogenic, radioactive diagnostic agent for intravenous 
administration, formulated in phosphate buffered sterile water for injection, and containing up to 
8% of ethanol. 
Name: 
 
2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]
 
pentyl)ureido)-pentanedioic acid 
Abbreviation:    
18F-DCFPyL 
Form:     
 
Sterile solution 
Administration: 
Intravenous 
Expiration: 
 
6 hours after end of synthesis 
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MSG is not regulated as a drug product in Canada. It is freely available on the market as a taste 
enhancer.  
3.7. 
18F-DCFPyL  
18F-DCFPyL is a radiopharmaceutical developed at Hopkins (43), with high accumulation in 
prostate cancer and favourable distribution for imaging (9). 18F-DCFPyL behaves like 68Ga-
PSMA, with higher standardized uptake value (SUV) in tumours (7). The routine production of 
18F-DCFPyL has recently been greatly simplified in recent years (44, 45). 
4. Rationale for Study 
Prostate cancer is the most common cancer affecting Canadian men and many men die from 
metastatic castration resistant prostate cancer (mCRPC), an incurable form of the disease. 
Lutetium-177 (177Lu) and Actinium-225 (225Ac) are Radioligands based on the EuK backbone, 
targeting the PSMA receptor, are highly promising to improve survival and quality of life in 
patients with mCRPC, but the main side effect is xerostomia, caused by the accumulation of 
these compounds in the salivary glands. MSG has proven effective, in large doses, to reduce 
off-target kidney and salivary gland accumulation of EuK based PSMA radioligands, without 
negatively affecting tumour uptake. We propose to use an imaging radiopharmaceutical, 18F-
DCFPyL, to investigate whether MSG can reduce off-target accumulation of PSMA radioligands.  
18F-DCFPyL will be used as a surrogate for 177Lu and 225Ac therapeutic radiopharmaceuticals. 
This way, if MSG is ineffective, affects tumour uptake, or has paradoxical effects by enhancing 
salivary gland accumulation, this will not adversely affect participants, as 18F delivers minimal 
radiation exposure and will not have any biological effects even if its biodistribution is altered by 
MSG. 
5. Risks and Benefits 
5.1. 
Radiation exposure 
A pilot study of 18F-DCFPyL in humans showed no serious adverse effects with 18F-DCFPyL 
administration. Minor adverse events were reported but none could be attributed to the 
radiotracer (9).   Participants will receive an effective radiation dose of 0.0165 mSv/MBq, which 
equates to 5.3 mSv for a typical adult injected dose of 320 MBq (7, 9). The radiation dose from 
the low-dose CT component of the PET/CT is approximately 3.9 - 7.8 mSv, dependent on body 
habitus.  The typical total absorbed dose to a participant from a 18F-DCFPyL PET/CT is 
approximately 8.8-16.4 mSv. As the participants will receive two 18F-DCFPyL PET/CT scans as 
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part of this study, the radiation exposure will be 17.6 to 32.8 mSv. This is considered acceptable 
for such studies in the adult population. For comparison, a typical diagnostic CT scan of the 
abdomen and pelvis provides 14 mSv of radiation exposure. 
As this is a sub-study of 18F-DCFPyL PET/CT research study, with an additional PET/CT scan 
and oral administration of MSG or placebo, there is no additional anticipated benefit from 
participants participating in this study. 
5.2. 
Oral MSG administration 
As discussed above, MSG is nontoxic, even in large quantities with a no adverse event limit of 
3.2 g/kg based on animal studies. The effects of MSG in humans are debated and have been 
extensively reviewed. Some studies have reported transient rise in blood pressure, headaches, 
dizziness and gastrointestinal disturbances such as nausea, when administered in doses in 
excess of 3 g. A potential link with asthma exacerbations has been suggested, but not 
substantiated. Large doses of MSG have been safely administered orally or intravenously in 
human participants, up to 12.7 g in a single oral dose or 125 mg/kg/day over several days.  
6. Mode of Administration and Dose 
18F-DCFPyL is injected intravenously using an intravenous catheter to avoid extravasation, 
following the procedures in REB protocol H16-01551 ([18F]-DCFPyL Positron Emission 
Tomography / Computed Tomography (PET/CT) for Assessment of Recurrent Prostate 
Cancer”). 
7. GCP and Regulatory Compliance 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines as set out by Health Canada and the UBC/BC Cancer Research Ethics Board (REB). 
8. Target Population 
Participants that are eligible to participate in study H16-01551 ([18F]-DCFPyL Positron Emission 
Tomography / Computed Tomography (PET/CT) for Assessment of Recurrent Prostate 
Cancer”). 
9. Trial Objective and Purpose 
The objective of this study is to evaluate the effects of oral MSG administration on the 
biodistribution of 18F-DCFPyL. The eventual purpose is to evaluate whether orally administered 
MSG is a suitable means of reducing adverse events and normal organ radiation exposure 
when PSMA-targeting radiopharmaceuticals are used to treat metastatic prostate cancer. 
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9.1. 
Hypothesis 
Orally administered MSG can significantly reduce lacrimal, salivary gland and renal 
accumulation of 18F-DCFPyL on PET/CT imaging. 
10. Trial Design 
10.1. 
Endpoints 
Primary endpoint: 
• 
To evaluate the effects of orally administered MSG on salivary gland accumulation of 
[18F]-DCFPyL. 
Secondary endpoints: 
• 
To evaluate the effects of MSG on renal accumulation of [18F]-DCFPyL. 
• 
To evaluate the effects of MSG on tumour accumulation of [18F]-DCFPyL. 
• 
To evaluate the tolerability and compliance with an orally administered solution of MSG. 
Study Design 
This is a prospective double blind intra-participant comparison of [18F]-DCFPyL PET/CT scans 
performed after orally administered MSG or placebo. 
The participants will receive oral administration of 12.7 g of MSG or placebo, in two different 
examination sessions, 30 minutes before [18F]-DCFPyL injection. 
10.2. 
Screening and Enrollment 
Participants will be contacted from the list of patients eligible for REB protocol H16-01551 ([18F]-
DCFPyL Positron Emission Tomography / Computed Tomography (PET/CT) for Assessment of 
Recurrent Prostate Cancer”). The patients will be invited to participate in this sub-study, with the 
clear understanding that declining to participate in this sub study will not affect their eligibility to 
participate in H16-01151. 
10.3. 
Obtaining Informed Consent 
To avoid any impression of coercion, the treating oncologist will not be involved in obtaining 
consent from participants directly. Following identification of potential research participants by 
their oncologist, the study coordinator will make contact with the potential participant via phone 
to discuss the research study and address any questions. Participants are informed that 
consent is entirely voluntary and that they can withdraw from the study at any time without 
explanation. They will also be informed that if they decline to participate in this sub-study, this 
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will not affect their eligibility to participate in H16-01151. They will be informed that participating 
in this sub-study will entail an additional visit to BC Cancer and an additional scan, and that they 
will be compensated financially for their time and inconvenience. They will continue to receive 
the best care at the British Columbia (BC) Cancer regardless of their decision to participate in 
the study. 
The study coordinator will obtain verbal consent over the phone and will schedule a PET scan 
appointment.  When the participant arrives for their scheduled appointment, a written informed 
consent will be obtained prior to the performance of any protocol-specified procedures, both for 
the main study (H16-01551) as well as this sub-study.  Participants will be given a copy of the 
signed consent forms for their own records. A screening log will be maintained to record every 
participant contacted to participate in the study. 
10.4. 
Assignment of Participant Identification Numbers  
The participant identification numbers will be established upon signature of the consent form, 
and will be consecutively numbered based on the template “MSG-XX-YYY-Z”, where XX 
represents the site code (01 in this case for BC Cancer), YYY represents the participant 
number, starting from 001 and numbered consecutively, and Z will be a letter (A or B) to identify 
whether this is the first or second scan performed as part of this study. The participants will also 
be assigned an additional study code based on the template required for protocol H16-01151. 
The placebo examination will be used for the purposes of protocol H16-01151. 
 
 
 
 
 
 
 
 
 
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10.5. 
Schematic Flow Diagram 
The procedure in blue is the additional PET/CT scan involved in this sub-study. The other 
components are part of protocol H16-01151. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.6. 
Measure to Minimize/Avoid Bias 
This is a randomized double blind study, and neither the participant nor the research coordinator 
collecting adverse events will know whether the participant received placebo or an oral dose of 
MSG. Clinical information will be extracted on case report forms (CRFs), labelled with the 
participant identification number. Each imaging data set will contain only the participant 
identification number, date of exam, and will be fully anonymized. The PET/CT images will be 
read and analyzed by a small group of board certified nuclear medicine physicians in a core 
laboratory to minimize interpretation bias. The readers will be blinded as to whether the 
participants received placebo or MSG. 
Identify prostate cancer 
patients eligible for protocol 
H16-01151.  
Provide participant 
with information 
sheet 
Study Coordinator 
obtains written, 
informed consent 
First 18F-
DCFPyL 
whole body 
PET/CT 
(placebo or 
MSG) 
Clinical follow-
up at 12, 24 
and 36 months 
Gold standard available 
for endpoint determination 
No gold standard available or 
upon physician request 
Repeat 18F-DCFPyL whole 
body PET/CT available 6 - 36 
months after initial 18F-
DCFPyL scan 
Second 
18F-DCFPyL 
whole body 
PET/CT 
(placebo or 
MSG) 
< 4 wks apart 
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10.7. 
Trial Procedures 
10.7.1. 18F-DCFPyL PET/CT 
Each participant will undergo two 18F-DCFPyL PET/CT scans.  Each of the 18F-DCFPyL PET/CT 
should be performed within 4 weeks of each other. In cases of unexpected delays due to 
radiotracer unavailability, instrument failure, or participant schedule, additional delays are 
permissible with authorization from the local site investigator, but every effort should be made to 
obtain the two scans as closely as possible in time. 
The overall procedures will follow that of the parent protocol (H16-01151) for each PET/CT 
scan, with the following changes:  
For the MSG study, food grade MSG (12.7 g) will be dissolved in 300 mL ± 5% low sodium 
tomato juice (Heinz 50% less salt), and administered orally before 18F-DCFPyL administration.  
For placebo administration, regular tomato juice (Heinz) will be used. 
Participants will be instructed to drink 300 mL ± 5% of tomato juice containing MSG or placebo 
starting 30 minutes prior to 18F-DCFPyL injection, preferably over a period of 15-30 minutes, 
subject to individual tolerance. Participants will be instructed to drink the entire solution. If the 
participants are unable to completely drink the solution, this will be noted and the residual 
volume will be measured to calculate the amount of MSG or placebo ingested. As with the 18F-
DCFPyL protocol, participants will be instructed to fast for 4 hours prior to the study.  
Upon arrival at the PET imaging department, participants will have their weight recorded and 
baseline vital signs (blood pressure, heart rate, and oxygen saturation level) measured prior to 
the start of MSG ingestion, immediately prior to 18F-DCFPyL injection and 5 to 15 minutes after 
injection. 
Each study participant will have an intravenous catheter inserted.  The participant will receive a 
bolus intravenous dose of 18F-DCFPyL from an approved supplier, at a dose of approximately 
296 MBq followed by a 5 to 20 mL normal saline flush. 
The participant will rest in a comfortable chair or bed for 60 minutes. After 60 min, the blood 
pressure, heart rate, and oxygen saturation levels will be recorded. The participants will be 
allowed to leave the Functional Imaging Department to get a meal of their choice.  The blood 
pressure, heart rate, and oxygen saturation levels will be recorded again two hours after 18F-
DCFPyL. Immediately before scanning, the participants will be taken to a designated washroom 
and asked to void.  
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The rest of the procedures will be identical to protocol H16-01151. The PET/CT image 
acquisition time will be approximately 30 minutes. 
Upon completion of the scan, participants will be free to leave the department and will be 
encouraged to drink 3 to 4 extra glasses of water by the end of the day to promote further 
clearance of any remaining radiotracer in the urinary tract. Overall, the study will take 
approximately 3.5 hours of the participant’s time for each scan.  
10.7.2. Clinical Assessment 
The clinical assessment will remain unchanged from the parent protocol. Only the placebo scan 
(unless the patient withdraws from this sub-study) will be used for data analysis in protocol H16-
01151. 
10.8. 
Study Duration and Follow-up Visits 
10.8.1. Study Duration 
This study will continue until all participants are enrolled, or protocol H16-01151 is discontinued 
whichever occurs first.  
10.8.2. Follow-up Assessments 
This will follow the procedures implemented for protocol H16-01151. 
24 hour follow-up 
As per parent study for protocol H16-01151, all participants will be requested to either return to 
the functional imaging department approximately 24 hours (acceptable range 16-28 hours) after 
the injection of 18F-DCFPyL or agree to be contacted by phone. The participants will be asked if 
they experienced any undesirable effects following the administration of 18F-DCFPyL, or in the 
intervening 24 hours. The local site attending nuclear medicine physician will then make an 
assessment as to whether these effects are likely related to 18F-DCFPyL administration. 
Other follow-up and subsequent 18F-DCFPyL imaging 
This remains unchanged from protocol H16-01151. 
Discontinuation Criteria for Individual Participants, Parts of Trial and Entire Trial 
Research participants may stop their participation in this sub-study at any time, without 
prejudice. If the treating oncologist believes that participating in this trial may cause prejudice to 
a participant, he or she can stop the participation of this research participant. The data from 
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participants with incomplete participation will be included in the final analysis for efficacy if there 
is sufficient information to clarify the status of 18F-DCFPyL findings. If the participant initially 
intends to participate in this sub-study but subsequently chooses to only undergo one of the two 
scans, the data from the scan that has been obtained (whether in the placebo or MSG group) 
will be reported clinically and used for data analysis in protocol H16-01151.  Participants who 
withdraw from the study will be replaced by other participants for the purpose of this sub-study 
so that a total of 10 participants with two scans (MSG and placebo) are enrolled. 
Given that there is already a good safety profile with 18F-DCFPyL as well as MSG, no serious 
adverse events are expected in this study. If, however, a serious adverse event is reported and 
attributed to the injection of 18F-DCFPyL, then as per protocol H16-01151, the 18F-DCFPyL 
scans will stop immediately until an investigation of the adverse event has been performed, as 
well as a review of the manufacturing, quality control data and procedures from the 18F-DCFPyL 
production site.  If a serious adverse event is reported and attributed to the ingestion of MSG, 
then this study will stop immediately until an investigation of the adverse event has been 
performed. If it is not clear whether the 18F-DCFPyL or the MSG causes the serious adverse 
event, both studies will stop until an investigation of the adverse event has been performed. All 
serious adverse events must be reported as described below. 
If funding for the study is discontinued or lapses due to unexpectedly slow accrual and attempts 
to obtain further funding fail, then the study may be interrupted and the results of participants 
accrued to date will be compiled and analyzed. 
11. Accountability Procedures for the Investigational Product 
The 
18F-DCFPyL product will be manufactured at the approved radiopharmaceutical 
manufacturing site under a Health Canada approved Clinical Trial Application (CTA). The 
manufacturer of the product is responsible to meet Health Canada requirements for sterility. All 
serious adverse events must be reported to the manufacturer of 18F-DCFPyL, and the local REB 
as described below. 
12. Trial Treatment Randomization Codes and Procedures for Breaking Codes 
All data will be anonymized. Nominal data will be replaced with the research participant code. 
The study site coordinator will keep a master list of participant identification data associated with 
the research participant code. This master list will be kept separate from the CRFs, and will be 
kept under lock and key. 
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For randomization, a computer generated random list will determine the order of the scans 
(MSG first, placebo first). Sealed envelopes will be prepared. A study coordinator or 
technologist not involved in measuring vital signs or collecting adverse events will prepare the 
tomato juice solution based on the randomization envelope. The rest of the team will not be 
informed of which tomato juice is used (placebo or MSG) but this information will be recorded 
and will be immediately accessible should a participant experience a severe adverse event. 
13. Data 
Nominal participant data will only be kept in the master list kept by the local site coordinator. 
The data collected in the CRF for participant demographic data will be the same as per protocol 
H16-01151. 
14. Selection and Withdrawal of Participants 
14.1. 
Record of Study Participants 
A confidential record will be maintained of all study participants, including all participants who 
were screened for the study but not actually studied under this protocol. This confidential record 
will include at least the participant’s name, hospital records number, and address in the event of 
an emergency, if any further follow-up is necessary. 
14.2. 
Participant Inclusion Criteria 
The same inclusion criteria for the primary study protocol H16-01151 will apply. 
14.3. 
Participant Exclusion Criteria 
The same inclusion criteria for the primary study protocol H16-01151 will apply, with the addition 
of the following: 
• 
Severe uncontrolled hypertension (systolic blood pressure above 140 mm Hg and 
diastolic blood pressure above 90 mm Hg, or systolic blood pressure above 180 mm 
Hg, or diastolic blood pressure above 110 mg Hg). Patients with controlled 
hypertension under medication are eligible. 
• 
History of severe asthma that has led to hospitalizations or emergency room visits. 
• 
History of intolerance to MSG. 
• 
History of severe headaches or migraines triggered by food or MSG. 
• 
Participants on a sodium/salt restricted diet due to other medical conditions. 
• 
No new treatment has started between the first and second 18F-DCFPyL PET/CT. 
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14.4. 
Participant Withdrawal 
Participants are free to withdraw from the study at any time. If a participant decides to withdraw 
during the PET/CT scan, they are brought out of the scanner immediately.  Just as if they had 
completed the scan, an appreciation for their time and effort invested in participating in this 
research will be expressed to the participant. If an injection of 18F-DCFPyL took place, the 
participant is reminded to drink 3 to 4 extra glasses of water by the end of the day to accelerate 
elimination of residual radioactivity from the urinary system. Data collected from the withdrawn 
participant will be used if there is sufficient information to evaluate the relative accuracy of the 
PET scan.  Participant withdrawal from the research study will not jeopardize the participant’s 
care.  
15. Treatment of Participants 
Not applicable. The participants will be treated by their care team according to routine 
procedures. Treatments are not affected by participation in this clinical trial, and participants 
recruited in this trial can participate in other research projects, as long as these projects do not 
interfere with the scheduling of the imaging studies. 
16. Study Materials 
Name:  
 
18F-DCFPyL  
Activity: 
 
296 - 521 MBq per participant 
Dosage Form:  
Sterile solution 
Product is prepared on a scheduled basis; the lot number of each product administered to each 
participant will be recorded on the dose slip or sticker.  The expiry date (6 hours after end of 
synthesis) is noted on the label. 
The study agent will be synthesized in-house in the radiopharmaceutical facility once all 
essential regulatory documents are available, including written approval from Health Canada 
and appropriate REB approval. 
The MSG used in this study will be the Ajinomoto Monosodium Glutamate Umami Seasoning in 
454g bags, obtained from a distributor. MSG is an unregulated taste enhancer in Canada and is 
available from grocery stores and food distributors. To ensure the safety and integrity of the 
product, bags of MSG will be kept under lock and key in a secure temperature and humidity 
controlled storage room used for manufacturing precursors for human clinical studies in the 
cyclotron radiopharmacy. 
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16.1. 
Authorized Suppliers  
BC Cancer - Vancouver, will be the authorized radiopharmaceutical facility authorized to 
manufacture 18F-DCFPyL, pending approval by Health Canada as part of a CTA. 
Ajinomoto Monosodium Glutamate Umami Seasoning in 454g bags, will be sourced via Amazon 
Canada. 
16.2. 
Preparation 
The study agent (18F-DCFPyL) is prepared in a shielded multi-dose vial. Using appropriate 
shielding and aseptic technique, the proper amount of 18F-DCFPyL will be drawn up into a 
sterile syringe. The final total dose will be measured in a dose calibrator and entered on the 18F-
DCFPyL dose slip/sticker. 
The MSG solution will be prepared by weighing 12.7 g of MSG in an empty disposable plastic 
glass, to which 300 mL ± 5% of Heinz low sodium tomato juice will be added. 
The placebo solution will be constituted of regular Heinz tomato juice. 
16.3. 
Packaging and Labelling 
18F-DCFPyL is supplied in a multi-dose, sterile, non-pyrogenic injection vial. The vial is labelled 
with an immediate surface label containing the name, lot number and date of preparation and an 
outer label containing the following: 
• 
Name and concentration (assay) of 18F-DCFPyL 
• 
Lot number 
• 
Calibration date and time 
• 
Total activity and total volume 
• 
Radiation warning symbol and “DANGER - RADIATION” 
• 
Store upright at room temperature (15-30°C) 
• 
Expiration period (6 hours after end of synthesis) 
• 
Manufacturer’s name and address 
 
A sample of each bag of MSG used in this study will be retained in case serious adverse events 
are reported by participants. 
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16.4. 
Storage and Disposition of Study Agent 
The multi-dose vial containing the 18F-DCFPyL will be stored at room temperature in a shielded 
area.  All regulations regarding the handling of radioactive material will be followed. 
The investigator or designee is responsible for ensuring that the 18F-DCFPyL is correctly 
dispensed and recorded, that the product is handled and stored safely and properly, and that it 
only be given to participants in accordance with this protocol.  Records of dispensing of 18F-
DCFPyL will be kept on a Study Medication Inventory Form. 
Unused and used 18F-DCFPyL containers must be reconciled and disposed of according to the 
trial site’s procedures for handling radioactive material. 
 
17. Assessment of Efficacy 
17.1. 
Efficacy Parameters 
Salivary gland and renal accumulation of [18F]-DCFPyL measured by the SUV. 
17.2. 
Methods for Assessing and Analyzing Efficacy 
18F-DCFPyL scans will be analysed as per protocol H16-01151. 
For determination of salivary gland and renal uptake, regions of interest will be drawn around 
the kidneys and salivary glands, using a standardized contouring method, to measure the SUV. 
The average SUV in the organs will be used for this analysis. Additional regions of interest will 
be placed on the 5 most active lesions on the scan, the circulating blood activity (from the left 
ventricle cavity), the liver, and skeletal muscles as background activity. 
 
18. Assessment of Safety 
18.1. 
Methods for Analyzing and Assessing Safety 
18F-DCFPyL quality will be determined so as to meet the approved specifications for production. 
All participants will be weighed prior to 18F-DCFPyL injection.  Before administration of MSG, 
before injection of 18F-DCFPyL, 5 to 15 minutes after 18F-DCFPyL injection and one and two 
hours after 18F-DCFPyL injection, vital signs (blood pressure, heart rate, oxygen saturation) will 
be recorded.  If there are concerns that the participant’s health status has changed prior to, 
during, or immediately following the PET/CT scan, a physician will provide a more detailed 
assessment.  There are no anticipated side effects from the 18F-DCFPyL injection itself.  
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18.2. 
Adverse Event Reporting 
The framework used for adverse reaction recording will be based on the American College of 
Radiology Imaging Network (ACRIN) guidelines published September, 2002 (revised May, 
2008). 
18.3. 
Site Responsibilities 
Each study investigator, study nurse and/or coordinator is responsible for the prompt reporting 
of adverse events.  The assignment of the event grade and association with the investigational 
drug is made by the study site investigator, and should be documented in the participant chart.  
An adverse event form must be completed within 30 days. Serious adverse events should be 
reported to the local REB within 48 hours following the event, and unexpected SAEs attributed 
to the study drug must be reported to Health Canada by fax at (613) 957-0364 within 7 days for 
a fatal or life-threatening event or 15 days for a non-fatal or non-life-threatening event. 
18.4. 
Definition of Adverse Event 
An Adverse Event (AE) is any untoward, undesired, unplanned medical occurrence in a 
participant and does not necessarily have a causal relationship with the study intervention. An 
adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding or physiological observations), symptom or disease temporally associated 
with the use of a medical treatment or procedure that may or may not be considered related to 
the medical treatment or procedure. Any symptom, sign, illness, or experience that develops or 
worsens in severity during the course of the study, including inter-current illnesses or injuries, 
should be regarded as an adverse event. 
18.5. 
Definition of Serious Adverse Event 
Adverse events are classified as serious or non-serious. A Serious Adverse Event (SAE) is 
defined as any untoward medical occurrence/AE that: 
• 
Results in death; 
• 
Is life-threatening (refers to any adverse event that places the participant at immediate 
risk of death from the event as it occurred; life-threatening event does not include an 
event that, had it occurred in a more severe form, might have caused death, but as it 
actually occurred, did not create an immediate risk of death);  
• 
Requires in-patient hospitalization and/or prolongation of an existing hospitalization 
(hospitalization refers to an overnight admission). Emergency room visits are not 
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considered serious until one of the above criteria is met. Any elective hospitalization for 
a pre-existing condition that has not worsened does not constitute an SAE; 
• 
Results in persistent or significant disability or incapacity (substantial disruption in a 
person’s ability to conduct normal daily living activities); a congenital anomaly or birth 
defect; or other medically important event.  
Important medical events are those based upon appropriate medical judgment that may not be 
immediately life threatening, but are clearly of major clinical significance. They may jeopardize 
the participant and may require intervention to prevent one of the other serious outcomes noted 
above.  If there is any doubt whether the adverse event constitute a serious adverse event, it 
should be treated as serious and reported. 
Grade refers to the severity (intensity) of the adverse event. 
1 - Mild: AE is noticeable to the participant but does not interfere with routine activity. 
2 - Moderate: AE interferes with routine activity but responds to symptomatic therapy/rest 
3 - Severe: AE significantly limits the participant’s ability to perform routine activities despite 
symptomatic therapy 
4 - Life-threatening or disabling 
5 - Death/Fatal 
18.6. 
Adverse Event Attribution 
Attribution is the determination of whether an adverse event is related to a study treatment or 
procedure.  An AE may be considered associated with the study treatment or procedure if there 
is a reasonable possibility that the adverse event was caused by the injected 18F-DCFPyL. An 
AE may be considered not associated with the study treatment/procedure if there is not a 
reasonable possibility that the AE was caused by participating in the study. 
Attribution categories are: 
Definite - AE is clearly related to the study treatment or procedure. 
Probable - AE is likely related to the study treatment or procedure. 
Possible - AE may be related to the study treatment or procedure. 
Unlikely - AE is doubtfully related to the study treatment or procedure. 
Unrelated - AE is clearly NOT related to the study treatment or procedure. 
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18.7. 
Expected Adverse Events from procedures 
Injection of 18F-DCFPyL 
• 
Bruising 
• 
Bleeding, or 
• 
Infection at the site of injection 
PET/CT scan 
• 
Discomfort, or 
• 
Claustrophobia 
MSG 
Anectodal evidence has linked MSG to the following symptoms, with no clear scientific evidence 
of causality: 
• 
Headache 
• 
Flushing 
• 
Sweating 
• 
Facial pressure or tightness 
• 
Numbness, tingling or burning in the face, neck and other areas 
• 
Heart palpitations 
• 
Chest pain 
• 
Nausea 
• 
Weakness 
Only AEs that are attributed to the study drug and are both serious and unexpected will be 
participant to expedited reporting to Health Canada and to the local REB. Each centre must 
adhere with the policy of documenting any AE, regardless of causality.  
18.8. 
Adverse Event Follow-up after 18F-DCFPyL 
The AE monitoring period in the protocol follows the American College of Radiology Imaging 
Network (ACRIN) recommendations of monitoring events until 10 half-lives of the agents. The 
study is conducted in participants with cancer who are likely to suffer from significant events 
related to their disease or toxicity caused by treatments unrelated to this research study. For 
this reason, ACRIN does not recommend extending the monitoring period further due to the risk 
of confounding investigational product AEs with treatment-related AEs.  AEs will be considered 
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related to this study if they occur within 10 half-lives (rounded up to the next day) following the 
administration of 18F-DCFPyL. Consequently, this would mean reporting AE occurring up to 24 
hours following administration.  
18.9. 
Type and Duration of Follow-up of Participants after Adverse Events 
An AE should be followed by the study site lead investigator until the event is resolved, the 
participant is lost to follow-up, the symptoms resolve, or the AE is found to be unrelated to the 
study. 
 
19. Statistics 
19.1. 
Description of statistical methods 
19.1.1. Statistical analyses 
The 18F-DCFPyL results will be analysed as comparison between the MSG and placebo 
subgroup. Standard descriptive statistics will be used for the SUV values, including mean, 
median, and standard deviation. 
SUV values will be assessed for normality and transformed using standard techniques such as 
square root or reciprocal transformation when appropriate.  If the data pass a normality test 
(D’Agostino normality test or other to be determined), organ uptake in the kidneys and salivary 
glands will be performed using a one-tailed paired t-test, with a p-value of 0.05 (the a priori 
hypothesis is a reduction in renal and salivary gland accumulation in the MSG group).  
If the data does not readily conform to a normal distribution, parametric analyses will be used, 
notably the Wilcoxon matched-pairs signed-rank test for the a priori hypotheses, and Dunn’s 
test for the other organs. 
As a supplemental analysis, since the SUV is a ratio that is normalized based on either lean 
body mass and the injected activity of the radiopharmaceutical, analysis of covariance will be 
performed with the organ uptake (kidney and salivary glands) as the dependent variable, with 
the treatment group as the independent variable, and body mass and injected activity as 
covariates. This will be performed looking as well at the lean body mass and body surface area 
as covariates instead of body weight. 
Safety parameters will be presented using descriptive statistics. 
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19.2. 
Sample Size Considerations 
A total of 10 participants in a paired experiment will be used for this study. In a preliminary 
analysis of 100 18F-DCFPyL scans performed to date, the SUV (based on body weight) in the 
parotid glands was 15.2 ± 4.7, while the SUV in the kidneys was 34.2 ± 12.7. Clinically, a 
reduction of 33% of more would be considered sufficiently significant to consider using an 
intervention such as MSG to reduce radiation dose to the salivary glands and kidneys. 
19.2.1. Primary endpoint 
The aim of this pilot study is to evaluate if a reduction in salivary gland accumulation of 18F-
DCFPyL can be achieved with MSG. A sample size of 10 achieves 100% power to detect a 
mean of paired differences of 5.0 (33%) with an estimated standard deviation of differences of 
1.0 and with a significance level (alpha) of 0.05 using a one-sided paired t-test. If the estimated 
standard deviation of differences is 5.0, a sample size of 10 achieves 90% power to detect a 
mean difference of 5.0 with an alpha of 0.05. These calculations were performed using NCSS 
Pass software, version 14.0.6, using the Paired Means Power Analysis tool. 
19.2.2. Secondary endpoints 
For the secondary analysis of renal accumulation, a sample size of 10 achieves 100% power to 
detect a mean of paired differences of 11.4 (33%) with an estimated standard deviation of 
differences of 2.0 and with a significance level (alpha) of 0.05 using a one-sided paired t-test. If 
the estimated standard deviation of differences is 10.0, a sample size of 10 achieves 95% 
power to detect a mean difference of 11.4 with an alpha of 0.05.  
 
Tumour uptake is highly variable among sites (due to size variations) and across participants, 
but expected to be reproducible to within 10% within participants and within target lesions, 
based on prior experience with 18F-FDG PET imaging on test-repeat experiments. A reduction 
of 10% or greater would be highly undesirable for the intervention.  Assuming a mean difference 
of 1.1 or greater, and standard deviation of the difference ranging from 0.1 to 1.0, the table 
below shows the power of the study: 
 
 
 
 
 
 
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Paired Means Power Analysis 
 
Numeric Results for Paired T-Test 
Null Hypothesis: Mean of Paired Differences = 0, Alternative Hypothesis: Mean of Paired Differences > 0 
Unknown standard deviation. 
 
 
 
 
 
Mean of Paired 
 
Effect 
Power 
N 
Alpha 
Beta 
Differences 
S 
Size 
1.00000 
10 
0.05000 
0.00000 
1.1 
0.1 
11.000 
1.00000 
10 
0.05000 
0.00000 
1.1 
0.5 
2.200 
0.94020 
10 
0.05000 
0.05980 
1.1 
1.0 
1.100 
 
For adverse events, simple descriptive statistics will be used. Differences in vital signs between 
the MSG and placebo groups will be performed using repeated measures analysis of variance. 
19.3. 
Criteria for the Termination of the Trial 
The trial will be terminated when participant accrual is complete for the primary objective, if 
severe adverse events are observed in the MSG group and the REB recommends interruption 
of the study, or if the primary protocol is terminated. 
19.4. 
Accounting for Missing, Unused and Spurious Data 
A minimum of two scans per participant will be required for this study for analysis (placebo vs 
MSG). Participants who have not completed two scans will be replaced by other participants. 
19.5. 
Procedures for Reporting Protocol Deviations 
Any deviation from the protocol must be reviewed and approved by the investigators listed on 
the title page of this protocol, and a request for acknowledgement must be submitted to the 
institution’s Research Ethics Board. 
19.6. 
Selection of Participants to be Included in the Analyses 
All evaluable participants will be included in the analyses. 
 
20. Direct Access to Source Data/ Documents 
The data gathered from the scans must be stored on a password protected computer system 
and hosted on a secure network at the study site.    
Participant study information including reconstructed PET/CT data stored on compact disc, 
consent forms and case report forms are filed and stored in a locked room at the study site.  
The identification numbers correlating with participant personal/medical information are kept as 
per medical records in a locked cabinet in a locked office.  Only study centre personnel may 
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have access to these records.  The local site REB, study sponsor and representatives from 
Health Canada may also review the records and this is indicated in the participant consent form. 
21. Data Management 
All procedures in the original approved parent protocol (H16-01551) apply to this study. 
 
22. Ethical Considerations 
All procedures in the original approved parent protocol (H16-01551) apply to this study.   
 
23. Regulatory Requirements and Investigator Obligations 
23.1. 
GCP and Investigator Compliance 
This study will be conducted in accordance with the principles of GCP guidelines as issued by 
the ICH (1996) and adopted by Canada in 1997. To ensure compliance with the guidelines, the 
study may be independently audited. The investigator agrees, by written consent to this 
protocol, to fully co-operate with compliance checks by allowing direct access to all 
documentation for authorized individuals. 
23.2. 
Documentation and Record-Keeping 
The investigator must maintain all study records, including participant medical records, for 25 
years after the completion or termination of this clinical trial. 
23.3. 
Premature Termination of the Study 
If the clinical study must be terminated for any reason whatsoever, the investigator will return all 
study agents and CRFs to the Sponsor, provide a written statement as to why the premature 
termination has taken place and notify the REB and Health Canada. 
23.4. 
Clinical Study Report / Publication 
All procedures in the original approved parent protocol (H16-01551) apply to this study.   
23.5. 
Compensation / Indemnification 
No funding is available to compensate participants for any injury related to procedures 
performed as part of this clinical trial.   
The investigator will retain any indemnification and insurance documents in the study file and 
these documents must be available for inspection by the REB and the regulatory authorities. 
 
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REIMBURSEMENT 
A reimbursement of up to $100 will be provided for out of pocket expenses such as 
transportation, parking, meals, etc. if receipts are kept and provided for reimbursement, for each 
scan.  
PAYMENTS TO PARTICIPANTS 
Since participants volunteer to undergo a second PET/CT scan as part of this study with no 
expected benefits, and the inconvenience of an IV injection, time spent in the facility, and 
potential minor undesirable effects of MSG, a compensation will be offered. Research 
participants will receive payment for the extra scan that they will undergo as part of this 
research study, prorated to the extent of their participation. In no case will payment be 
conditional on completion of the entire study. If participants withdraw early, they will be 
compensated in proportion to their participation as per below.  
Payment is calculated on the following basis and based on an average hourly salary rate in 
Canada in 2016 of $27.70 per hour. 
3.5 hours of participant time x $27.70 = $100 
Injection: $50 
Radiation exposure: $100 
Total maximum: $250.00 per participant 
 
23.6. 
Protocol Amendments 
Changes to a protocol must be implemented by a formal protocol amendment.  A formal 
amendment, drafted, and approved by the Principal Investigator, must be approved by the REB 
prior to implementation of the amendment. 
In the case where the original clinical trial was submitted to Health Canada as a CTA, and the 
protocol amendment will affect (1) the selection, criteria for selection, monitoring or dismissal of 
a clinical trial participant; (2) the evaluation of the clinical efficacy of the drug, (3) alter the risk to 
the health of a clinical trial participant; (4) the safety evaluation of the drug or (5) extend the 
duration of the clinical trial, Health Canada must approve these changes, by means of a CTA 
amendment, before they are implemented.  If the protocol amendment does not affect any of the 
5 aspects of a clinical trial outlined above, the changes may be implemented immediately, but 
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Health Canada must be informed in writing, by means of a Notification, within 15 calendar days 
after the date of implementation of the amendment. 
In some instances, an amendment may require a change to a consent form.  The investigator 
must receive REB approval of the revised consent form prior to implementation of the 
amendment. In addition, changes to the CRFs, if required, will be incorporated in the 
amendment. 
A modification to the protocol may be initiated without REB or Health Canada approval ONLY 
when the change is necessary to eliminate an apparent immediate hazard to the participants 
and on approval by the Principal Investigator.  In that event, the investigator must notify the REB 
in writing within five (5) working days after implementation and the Principal Investigator must 
supply Health Canada with a CTA amendment or Notification, as appropriate, within 15 days 
after implementation. 
24. Financing and Insurance 
 All procedures in the original approved parent protocol (H16-01551) apply to this study.   
25. Supplements 
The following documents contain important information on this protocol: 
• 
Main consent form for  - 18F-DCFPyL Positron Emission Tomography / Computed 
Tomography (PET/CT) for Assessment of Recurrent Prostate Cancer 
• 
Protocol H16-01551 ([18F]-DCFPyL Positron Emission Tomography / Computed 
Tomography (PET/CT) for Assessment of Recurrent Prostate Cancer”) 
• 
Sub-study consent form - Participant Information and Consent Form – Evaluation of 
monosodium glutamate (MSG) to reduce salivary gland and renal accumulation of 
PSMA-binding radiopharmaceuticals 
• 
Investigator’s brochure for 18F-DCFPyL injection 
 
26. References 
1. 
Sweat SD, Pacelli A, Murphy GP, Bostwick DG. Prostate-specific membrane antigen 
expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology. 1998 
Oct;52(4):637-40. PubMed PMID: 9763084. Epub 1998/10/08. 
2. 
Liu H, Moy P, Kim S, Xia Y, Rajasekaran A, Navarro V, et al. Monoclonal antibodies to 
the extracellular domain of prostate-specific membrane antigen also react with tumor vascular 
endothelium. Cancer Res. 1997 Sep 1;57(17):3629-34. PubMed PMID: 9288760. Epub 
1997/09/01. 
Short Title: MSG in PSMA imaging 
 
Page 34 of 38 
Document Date: October 12, 2018 
 
Version: 1.0  

3. 
Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA - PET in prostate 
cancer 
management. 
Nat 
Rev 
Urol. 
2016 
Apr;13(4):226-35. 
PubMed 
PMID: 
WOS:000374429800008. English. 
4. 
Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, et al. The 
diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the 
diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015 Feb;42(2):197-209. 
PubMed PMID: 25411132. Pubmed Central PMCID: PMC4315487. Epub 2014/11/21. 
5. 
Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of 
Hybrid (6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After 
Radical Prostatectomy. Journal of nuclear medicine : official publication, Society of Nuclear 
Medicine. 2015 May;56(5):668-74. PubMed PMID: 25791990. Epub 2015/03/21. 
6. 
Giesel FL, Will L, Kesch C, Freitag M, Kremer C, Merkle J, et al. Biochemical 
Recurrence of Prostate Cancer: Initial Results with [(18)F]PSMA-1007 PET/CT. Journal of 
nuclear medicine : official publication, Society of Nuclear Medicine. 2018 Apr;59(4):632-5. 
PubMed PMID: 29419475. Epub 2018/02/09. 
7. 
Dietlein M, Kobe C, Kuhnert G, Stockter S, Fischer T, Schomacker K, et al. Comparison 
of [(18)F]DCFPyL and [ (68)Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with 
Relapsed Prostate Cancer. Mol Imaging Biol. 2015 Aug;17(4):575-84. PubMed PMID: 
26013479. Pubmed Central PMCID: PMC4493776. Epub 2015/05/28. 
8. 
Rowe SP, Macura KJ, Mena E, Blackford AL, Nadal R, Antonarakis ES, et al. PSMA-
Based [(18)F]DCFPyL PET/CT Is Superior to Conventional Imaging for Lesion Detection in 
Patients with Metastatic Prostate Cancer. Mol Imaging Biol. 2016 Jun;18(3):411-9. PubMed 
PMID: 27080322. Pubmed Central PMCID: PMC5261857. Epub 2016/04/16. 
9. 
Szabo Z, Mena E, Rowe SP, Plyku D, Nidal R, Eisenberger MA, et al. Initial Evaluation 
of [(18)F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of 
Prostate Cancer. Mol Imaging Biol. 2015 Aug;17(4):565-74. PubMed PMID: 25896814. Pubmed 
Central PMCID: PMC4531836. Epub 2015/04/22. 
10. 
Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schafers M, Essler M, et al. 
German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced 
Prostate Cancer Patients. Journal of nuclear medicine : official publication, Society of Nuclear 
Medicine. 2017 Jan;58(1):85-90. PubMed PMID: 27765862. 
11. 
Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, et al. 
Targeted alpha-Therapy of Metastatic Castration-Resistant Prostate Cancer with (225)Ac-
PSMA-617: Dosimetry Estimate and Empiric Dose Finding. Journal of nuclear medicine : official 
publication, Society of Nuclear Medicine. 2017 Oct;58(10):1624-31. PubMed PMID: 28408529. 
12. 
Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [(177)Lu]-
PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate 
cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018 
Jun;19(6):825-33. PubMed PMID: 29752180. Epub 2018/05/13. 
13. 
Sheikhbahaei S, Afshar-Oromieh A, Eiber M, Solnes LB, Javadi MS, Ross AE, et al. 
Pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (PSMA)-
targeted PET imaging. European journal of nuclear medicine and molecular imaging. 2017 
Nov;44(12):2117-36. PubMed PMID: 28765998. 
14. 
Rathke H, Giesel FL, Flechsig P, Kopka K, Mier W, Hohenfellner M, et al. Repeated 
(177)Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq. 
Short Title: MSG in PSMA imaging 
 
Page 35 of 38 
Document Date: October 12, 2018 
 
Version: 1.0  

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018 
Mar;59(3):459-65. PubMed PMID: 28798031. Epub 2017/08/12. 
15. 
Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, et al. 
Targeted alpha-Therapy of Metastatic Castration-Resistant Prostate Cancer with (225)Ac-
PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control. 
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018 
May;59(5):795-802. PubMed PMID: 29326358. Epub 2018/01/13. 
16. 
Delker A, Fendler WP, Kratochwil C, Brunegraf A, Gosewisch A, Gildehaus FJ, et al. 
Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of 
metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2016 Jan;43(1):42-51. PubMed PMID: 
26318602. Epub 2015/09/01. 
17. 
Kratochwil C, Giesel FL, Stefanova M, Benesova M, Bronzel M, Afshar-Oromieh A, et al. 
PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 
177Lu-Labeled PSMA-617. Journal of nuclear medicine : official publication, Society of Nuclear 
Medicine. 2016 Aug;57(8):1170-6. PubMed PMID: 26985056. Epub 2016/03/18. 
18. 
Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo RK, Seth A, et al. Post-therapeutic 
dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-
resistant prostate cancer. Nucl Med Commun. 2017 Jan;38(1):91-8. PubMed PMID: 27782913. 
Epub 2016/10/27. 
19. 
Kabasakal L, AbuQbeitah M, Aygun A, Yeyin N, Ocak M, Demirci E, et al. Pre-
therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific 
membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur J 
Nucl Med Mol Imaging. 2015 Dec;42(13):1976-83. PubMed PMID: 26227531. Epub 2015/08/01. 
20. 
Kratochwil C, Giesel FL, Leotta K, Eder M, Hoppe-Tich T, Youssoufian H, et al. PMPA 
for nephroprotection in PSMA-targeted radionuclide therapy of prostate cancer. Journal of 
nuclear medicine : official publication, Society of Nuclear Medicine. 2015 Feb;56(2):293-8. 
PubMed PMID: 25613537. 
21. 
Chatalic KL, Heskamp S, Konijnenberg M, Molkenboer-Kuenen JD, Franssen GM, 
Clahsen-van Groningen MC, et al. Towards Personalized Treatment of Prostate Cancer: PSMA 
I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent. 
Theranostics. 2016;6(6):849-61. PubMed PMID: 27162555. Pubmed Central PMCID: 4860893. 
22. 
Matteucci F, Mezzenga E, Caroli P, Di Iorio V, Sarnelli A, Celli M, et al. Reduction of 
(68)Ga-PSMA renal uptake with mannitol infusion: preliminary results. European journal of 
nuclear medicine and molecular imaging. 2017 Dec;44(13):2189-94. PubMed PMID: 28801787. 
23. 
Baum RP, Langbein T, Singh A, Shahinfar M, Schuchardt C, Volk GF, et al. Injection of 
Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy: an 
Empirical Proof of a Promising Concept. Nuclear medicine and molecular imaging. 2018 
Feb;52(1):80-1. PubMed PMID: 29391917. Pubmed Central PMCID: 5777965. 
24. 
Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. 89Zr-DFO-
J591 for immunoPET of prostate-specific membrane antigen expression in vivo. Journal of 
nuclear medicine : official publication, Society of Nuclear Medicine. 2010 Aug;51(8):1293-300. 
PubMed PMID: 20660376. Pubmed Central PMCID: PMC2998794. Epub 2010/07/28. 
25. 
Israeli RS, Powell CT, Corr JG, Fair WR, Heston WD. Expression of the prostate-specific 
membrane antigen. Cancer Res. 1994 Apr 1;54(7):1807-11. PubMed PMID: 7511053. Epub 
1994/04/01. 
Short Title: MSG in PSMA imaging 
 
Page 36 of 38 
Document Date: October 12, 2018 
 
Version: 1.0  

26. 
Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific 
membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997 
Jan;3(1):81-5. PubMed PMID: 9815541. Epub 1997/01/01. 
27. 
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. 
Proteomics. Tissue-based map of the human proteome. Science (New York, NY). 2015 Jan 
23;347(6220):1260419. PubMed PMID: 25613900. Epub 2015/01/24. eng. 
28. 
Human 
Protein 
Atlas. 
2018 
[cited 
2018 
July 
16, 
2018]. 
Available 
from: 
www.proteinatlas.org. 
29. 
Hodson NA, Linden RW. The effect of monosodium glutamate on parotid salivary flow in 
comparison to the response to representatives of the other four basic tastes. Physiology & 
behavior. 2006 Dec 30;89(5):711-7. PubMed PMID: 17028046. 
30. 
Maluly HDB, Arisseto-Bragotto AP, Reyes FGR. Monosodium glutamate as a tool to 
reduce sodium in foodstuffs: Technological and safety aspects. Food science & nutrition. 2017 
Nov;5(6):1039-48. PubMed PMID: 29188030. Pubmed Central PMCID: 5694874. 
31. 
Rousseau E, Lau J, Kuo H-T, Zhang Z, Merkens H, Hundal-Jabal N, et al. Monosodium 
glutamate reduces 68Ga-PSMA-11 uptake in salivary glands and kidneys in preclinical prostate 
cancer model. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 
2018;In Press. 
32. 
Kwok RH. Chinese-restaurant syndrome. The New England journal of medicine. 1968 
Apr 4;278(14):796. PubMed PMID: 25276867. Epub 1968/04/04. eng. 
33. 
Obayashi Y, Nagamura Y. Does monosodium glutamate really cause headache? : a 
systematic review of human studies. The journal of headache and pain. 2016;17:54. PubMed 
PMID: 27189588. Pubmed Central PMCID: PMC4870486. Epub 2016/05/18. eng. 
34. 
Mortensen A, Aguilar F, Crebelli R, Domenico AD, Dusemund B, Frutos MJ, et al. Re‐
evaluation of glutamic acid (E 620), sodium glutamate (E 621), potassium glutamate (E 622), 
calcium glutamate (E 623), ammonium glutamate (E 624) and magnesium glutamate (E 625) as 
food additives. EFSA Journal. 2017;15(7):e04910. 
35. 
TOXNET Toxicology Data Network: Monosodium Glutamate [Internet]. 2007 [cited May 
1st, 
2018]. 
Available 
from: 
https://toxnet.nlm.nih.gov/cgi-
bin/sis/search/a?dbs+hsdb:@term+@DOCNO+580. 
36. 
Walker R, Lupien JR. The safety evaluation of monosodium glutamate. J Nutr. 2000 
Apr;130(4S Suppl):1049S-52S. PubMed PMID: 10736380. Epub 2000/03/29. 
37. 
US Food and Drug Administration. Questions and Answers on Monosodium glutamate 
(MSG). 
38. 
Vidlund M, Hakanson E, Friberg O, Juhl-Andersen S, Holm J, Vanky F, et al. 
GLUTAMICS--a randomized clinical trial on glutamate infusion in 861 patients undergoing 
surgery for acute coronary syndrome. The Journal of thoracic and cardiovascular surgery. 2012 
Oct;144(4):922-30.e7. PubMed PMID: 22721612. Epub 2012/06/23. eng. 
39. 
Fernstrom JD, Cameron JL, Fernstrom MH, McConaha C, Weltzin TE, Kaye WH. Short-
term neuroendocrine effects of a large oral dose of monosodium glutamate in fasting male 
subjects. The Journal of clinical endocrinology and metabolism. 1996 Jan;81(1):184-91. 
PubMed PMID: 8550750. Epub 1996/01/01. 
40. 
Chevassus H, Renard E, Bertrand G, Mourand I, Puech R, Molinier N, et al. Effects of 
oral monosodium (L)-glutamate on insulin secretion and glucose tolerance in healthy volunteers. 
Short Title: MSG in PSMA imaging 
 
Page 37 of 38 
Document Date: October 12, 2018 
 
Version: 1.0  

British journal of clinical pharmacology. 2002 Jun;53(6):641-3. PubMed PMID: 12047489. 
Pubmed Central PMCID: PMC1874333. Epub 2002/06/06. eng. 
41. 
Shimada A, Baad-Hansen L, Castrillon E, Ghafouri B, Stensson N, Gerdle B, et al. 
Differential effects of repetitive oral administration of monosodium glutamate on interstitial 
glutamate concentration and muscle pain sensitivity. Nutrition (Burbank, Los Angeles County, 
Calif). 2015 Feb;31(2):315-23. PubMed PMID: 25592010. Epub 2015/01/17. eng. 
42. 
Toda Y, Nakagita T, Hayakawa T, Okada S, Narukawa M, Imai H, et al. Two distinct 
determinants of ligand specificity in T1R1/T1R3 (the umami taste receptor). J Biol Chem. 2013 
Dec 27;288(52):36863-77. PubMed PMID: 24214976. Pubmed Central PMCID: PMC3873546. 
Epub 2013/11/12. 
43. 
Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, et 
al. 2-(3-{1-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]-Pentyl}-Ureido)-Pentanedioic 
Acid, [18F]DCFPyL, a PSMA-Based PET Imaging Agent for Prostate Cancer. Clinical Cancer 
Research. 2011;17(24):7645. 
44. 
Bouvet V, Wuest M, Jans HS, Janzen N, Genady AR, Valliant JF, et al. Automated 
synthesis of [(18)F]DCFPyL via direct radiofluorination and validation in preclinical prostate 
cancer models. EJNMMI research. 2016 Dec;6(1):40. PubMed PMID: 27142881. Pubmed 
Central PMCID: 4854855. 
45. 
Dornan MH, Simard JM, Leblond A, Juneau D, Delouya G, Saad F, et al. Simplified and 
robust one-step radiosynthesis of [(18) F]DCFPyL via direct radiofluorination and cartridge-
based purification. J Labelled Comp Radiopharm. 2018 May 2. PubMed PMID: 29722070. Epub 
2018/05/04. 
 
 
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