[18F]FALLYPRIDE FOR INJECTION: PRECURSOR AND REFERENCE
COMPOUND − ACCEPTANCE TESTING AND FORMS
PET Radiopharmaceutical Sciences Section,
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
1.
Date of review: 05/17/04
Source of precursor (tosyl-fallypride) for production of [18F]Fallypride for Injection
The
precursor
[(S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-toluenesulfonyloxy-propyl)-2,3-dimethoxy-
benzamide, 1] is supplied by Advanced Biochemical Compounds (ABX, Radeberg, Germany). The
synthesis, as reported in the literature (ref. 1), is summarized in the following scheme. The substituted
benzoic acid 2, (S)-2-(aminomethyl)-N-allylpyrrolidine 3 and pyridine are dissolved in chloroform,
cooled at 0° C and treated with N,N’-dicyclohexylcarbodiimide. After reaction overnight at room
temperature, work-up and purification, the substituted alcohol benzamide, (S)-N-[(1-allyl-2pyrrolidinyl)methyl]-5-(3-hydroxyropyl)-2,3-dimethoxybenzamide 4, is obtained.
This alcohol plus
pyridine in dichloromethane are then treated with p-toluenesulfonyl chloride. After reaction and work
up the tosylate precursor 1 is obtained.
Figure 1. Preparation of tosyl-fallypride
2.
The chiral purity of precursor (tosyl-fallypride) for production of [18F]Fallypride for Injection
The chiral purity of [18F]fallypride is dictated by the chiral purity of the precursor, (S)-tosyl-fallypride, used
in its radiosynthesis. The chiral purity of the (S)-tosyl-fallypride traces back to the chiral purity of the
natural amino acid, (S)-proline used by ABX in its synthesis via the derivative, (S)-2-aminomethyl)-Nallylpyrrolidine (Document 7, page 1)]. ABX obtains (S)-proline from Sigma Aldrich Chem Co with a chiral
purity of 99+% (see Aldrich catalog, cat. # 13,154-7). All steps in the synthesis of (S)-tosyl fallypride and
its conversion into [18F]fallypride via nucleophilic substitution with [18F]fluoride (at a site distal to the chiral
center) are incapable of causing racemisation at the C-2 pyrrolidinyl carbon, so that the chiral purity of
(S)-tosyl-fallypride is assured by the chiral purity of (S)-proline (chiral purity > 99+%).
Document 7. [18F]Fallypride for Injection: Precursor and Reference Compound − Acceptance Testing and Form
Page 1 of 6
[18F]FALLYPRIDE FOR INJECTION: PRECURSOR AND REFERENCE
COMPOUND − ACCEPTANCE TESTING AND FORMS
PET Radiopharmaceutical Sciences Section,
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
Date of review: 05/17/04
3. Acceptance criteria for precursor and reference compound
(A) Precursor
Source: the starting material (tosyl-fallypride) is obtained from ABX Advanced Biochemical
Compounds (Radeberg, Germany).
Acceptance criteria: the acceptance criteria for precursor are as follows:

Certificate of analysis from ABX Advanced Biochemical Compounds to confirm the identity and
purity of tosyl-fallypride.

Certificate of analysis from Sigma-Aldrich Chem. Co. to confirm the chiral purity of (S)-Proline.

1H-NMR
spectrum of tosyl-fallypride from ABX Advanced Biochemical Compounds to verify
chemical structure and that purity is ≥ 90%.

LC-MS of tosyl-fallypride performed in the PET Radiopharmaceutical Sciences Section on the
Finnigan LCQDeca LC/MSn (ThermoQuest, Germany) to confirm chemical structure and purity

HPLC in the PET Radiopharmaceutical Sciences Section showing the chemical purity of
precursor to be ≥ 90%.
(B) Reference compound
Source: the reference compound (Fallypride) is obtained from ABX Advanced Biochemical
Compounds (Radeberg, Germany).
Acceptance criteria: the acceptance criteria for reference compound are as follows:

Certificate of analysis from ABX Advanced Biochemical Compounds to confirm the identity and
purity of fallypride.

1H-NMR
spectrum of fallypride from ABX Advanced Biochemical Compounds to confirm that the
chemical structure is right and the purity is ≥ 90%.

LC-MS of fallypride performed in the PET Radiopharmaceutical Sciences Section on the Finnigan
LCQDeca LC/MSn (ThermoQuest, Germany) to confirm chemical structure and purity

HPLC in the PET Radiopharmaceutical Sciences (MIB, NIMH, NIH) showing the chemical purity
of fallypride to be ≥ 90%.
4. Precursor and reference compounds acceptance forms
See next page.
Document 7. [18F]Fallypride for Injection: Precursor and Reference Compound − Acceptance Testing and Form
Page 2 of 6
[18F]FALLYPRIDE FOR INJECTION: PRECURSOR AND REFERENCE
COMPOUND − ACCEPTANCE TESTING AND FORMS
PET Radiopharmaceutical Sciences Section,
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
Date of review: 05/17/04
Reference:
1. Mukherjee J., Yang Z-Y., Das M.K. and Brown T. (1995) Fluorinated benzamide neuroleptics – III.
Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3-dimethoxybenzamide as an improved dopamine D-2 receptor tracer. Nucl. Med. Biol., 22: 283-296.
Approved by: __________________________ Initials___________
Date:__________
Victor W Pike, Ph.D., Chief, PET Radiopharmaceutical Sciences, NIMH
Precursor Compound Acceptance Form
Receipt of compound:
Compound name: tosyl-fallypride
Lot #
Supplier name: ABX Advanced Biochemical
Catalog #
Compounds
Date received:
Quantity:
Molecular formula: C27H36N2O6S
Certificate of analysis: YES____ NO______
Molecular weight: 516.65
Chemical purity reported:
Attached documents, acceptance criteria and test results:
1. Certificates of Analysis from (1) ABX Advanced Biochemical and (2) Sigma-Aldrich Chem. Co.
2
attached?
YES_________ NO__________.
1H-NMR
YES_________ NO__________.
spectrum from supplier attached?
3. LC-MS data from this laboratory?
YES_________ NO__________.
4. HPLC chromatogram from this laboratory?
YES_________ NO__________.
(An example of a set of satisfactory attached documents is included in Document 9: Validation Runs).
Document 7. [18F]Fallypride for Injection: Precursor and Reference Compound − Acceptance Testing and Form
Page 3 of 6
[18F]FALLYPRIDE FOR INJECTION: PRECURSOR AND REFERENCE
COMPOUND − ACCEPTANCE TESTING AND FORMS
PET Radiopharmaceutical Sciences Section,
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
Chemical structure:
Date of review: 05/17/04
Acceptance criteria:
1. Identity: confirmed by 1H-NMR
2. Purity: > 90% by HPLC.
Test Results
Test
Results
Procedure
Date
Initials
1. NMR (ABX)
2. LC-MS (This laboratory)
3. HPLC (This laboratory)
SOP # QA308
Checked by:
Accepted by:
Storage condition:
Date
Document 7. [18F]Fallypride for Injection: Precursor and Reference Compound − Acceptance Testing and Form
Page 4 of 6
[18F]FALLYPRIDE FOR INJECTION: PRECURSOR AND REFERENCE
COMPOUND − ACCEPTANCE TESTING AND FORMS
PET Radiopharmaceutical Sciences Section,
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
Date of review: 05/17/04
Approved by: __________________________ Initials___________
Date:__________
Victor W Pike, Ph.D., Chief, PET Radiopharmaceutical Sciences, NIMH
Fallypride Reference Compound Acceptance Form
Receipt of compound:
Compound name: fallypride
Lot #
Supplier name: ABX Advanced Biochemical Compounds,
Catalog #
Date received:
Quantity:
Molecular formula: C20H29FN2O3
Molecular weight: 364.45 (free base)
Certificate of analysis: YES____ NO______
Chemical purity reported:
Attached documents, acceptance criteria and test results:
1 Certificate of analysis from supplier attached?
2
1H-NMR
YES_________ NO__________.
spectrum from supplier attached?
YES_________ NO__________.
3 LC-MS data from this laboratory?
YES_________ NO__________.
4 HPLC Chromatogram from this laboratory attached?
YES_________ NO__________.
(An example of a set of satisfactory attached documents is included in Document 9: Validation Runs).
Chemical structure:
Acceptance criteria:
1. Identity: confirmed by 1H-NMR
2. Purity: > 90% by HPLC
Document 7. [18F]Fallypride for Injection: Precursor and Reference Compound − Acceptance Testing and Form
Page 5 of 6
[18F]FALLYPRIDE FOR INJECTION: PRECURSOR AND REFERENCE
COMPOUND − ACCEPTANCE TESTING AND FORMS
PET Radiopharmaceutical Sciences Section,
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
Date of review: 05/17/04
Test results
Test
Results
Procedure
Date
Initials
1. NMR (ABX)
2. LC-MS (This laboratory)
3. HPLC (This laboratory)
SOP # QA308
Checked by:
Accepted by:
Storage condition:
Date
Document 7. [18F]Fallypride for Injection: Precursor and Reference Compound − Acceptance Testing and Form
Page 6 of 6