Pharmacological and Toxicological Evaluation of 2-Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-A-85380), a Ligand for Imaging Cerebral Nicotinic Acetylcholine Receptors with Positron Emission Tomography

  1. D. Bruce Vaupel,
  2. Srihari R. Tella,
  3. David L. Huso,
  4. Valentine O. Wagner III,
  5. Alexey G. Mukhin,
  6. Svetlana I. Chefer,
  7. Andrew G. Horti,
  8. Edythe D. London,
  9. Andrei O. Koren and
  10. Alane S. Kimes
  1. Neuroimaging Research Branch (D.B.V., A.G.M., S.I.C., A.G.H., A.S.K.), Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, Baltimore, Maryland; Department of Pharmacology (S.R.T.), Georgetown University Medical Center, Washington, D.C.; Department of Comparative Medicine (D.L.H.), Johns Hopkins University School of Medicine, Baltimore, Maryland; BioReliance, Inc. (V.O.W.), Rockville, Maryland; Departments of Psychiatry and Biobehavioral Sciences (E.D.L., A.O.K.), Molecular and Medical Pharmacology (E.D.L.), and the Brain Research Institute (E.D.L.), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
  1. Address correspondence to.
    Dr. D. Bruce Vaupel, NIDA IRP, Neuroimaging Research Branch, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: bvaupel{at}intra.nida.nih.gov

Abstract

2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380), a positron emission tomography (PET) radioligand for neuronal α4β2* nicotinic acetylcholine receptors, was evaluated for its pharmacology and safety. In the Ames test for mutagenicity, 2-F-A-85380 was without effect in five bacterial strains. No evidence of gross pathology or histopathological changes occurred in either 2-day acute (0.4-4000 nmol/kg i.v.) or 14-day expanded acute (40-4000 nmol/kg i.v.) toxicity studies in mice. Similarly, hematology and serum chemistry values in rhesus monkeys administered 60 nmol/kg i.v. were not affected over 14 days. Like nicotine, 2-F-A-85380 produced convulsions in mice at very high doses. The ED50 value of 2-F-A-85380 for eliciting tonic-clonic convulsions (5.0 μmol/kg i.v.) was nearly 4 times greater than that of nicotine (ED50 = 1.4 μmol/kg i.v.). Lower doses of 2-F-A-85380 (30-300 nmol/kg i.v.) and nicotine (20-400 nmol/kg i.v.) increased systolic and diastolic blood pressure, heart rate, and cardiac contractility in rats. Notably, the PR, QRS, or QTc intervals of the rat electrocardiogram were unaffected by either drug. Dosimetry studies indicated that the urinary bladder wall was the critical organ and total radiation exposure was within acceptable limits. Estimated doses of 2-F-A-85380 required to elevate blood pressure and heart rate by 10% ranged from 40 to 58 nmol/kg i.v. Nevertheless, the estimated radiopharmaceutically relevant dose of [18F]2-F-A-8380 required for initial PET imaging studies, 10 pmol/kg, is less than 1/4000th of the doses calculated (40-58 nmol/kg i.v.) to elevate blood pressure and heart rate by 10% in humans and should elicit no clinically significant effects and have acceptable dosimetry.

Footnotes

  • This study was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA). Dr. David L. Huso was supported in part by National Institutes of Health Grants RR000171 and CA062924. We also thank Drs. David McCann and James Terrill of NIDA for providing financial resources to acquire the bacterial reverse mutation assay.

  • Preliminary reports of this work were presented previously: Vaupel DB, London ED, Horti AG, Koren AO, Mukhin AG, Chefer SI, Pavlova OA, Stratton M, Huso DL, Tella SR, et al. (2002) 2[F-18]F-A-85380 acquires phase I approval as a radiotracer for imaging alpha4beta2 nicotinic receptors in human PET studies (Abstract 704). Drug Alcohol Depend66:S187, College of Problems on Drug Dependence, 2002; and Vaupel DB, Koren AO, and Tella S (2001) Radiotracers for imaging nicotinic acetylcholine receptors (nACHRs): electrocardiogram effects of 5-I-A-85380 (5IA), 2-F-A-85380 (2FA), and nicotine. Program 240.2, Abstract Viewer, Society for Neuroscience, 2001.

  • doi:10.1124/jpet.104.073999.

  • ABBREVIATIONS: 2-[18F]F-A-85380, 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine; PET, positron emission tomography; nAChR, nicotinic acetylcholine receptor; 5-[123I]I-A-85380, [123I]5-iodo-3-(2(S)-azetidinylmethoxy)pyridine; A-85380, 3-(2(S)-azetidinylmethoxy)pyridine; ANOVA, analysis of variance; CL, confidence limit; HTC, hematocrit.

    • Received July 27, 2004.
    • Accepted August 26, 2004.
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  1. Published online before print August 26, 2004, doi: 10.1124/jpet.104.073999 JPET January 2005 vol. 312 no. 1 355-365
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