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
Abstract
2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]F-A-85380), a positron emission tomography (PET) radioligand for neuronal alpha4beta2(*) 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 ED(50) value of 2-F-A-85380 for eliciting tonic-clonic convulsions (5.0 micromol/kg i.v.) was nearly 4 times greater than that of nicotine (ED(50) = 1.4 micromol/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 [(18)F]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.
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[3H]2-FA-85380 binds selectively to β2-containing nAChRs.
“In contrast, [3H]2-FA-85380 binds selectively to b2-containing nAChRs (Brody et al, 2006; Deuther-Conrad et al, 2006; Vaupel et al, 2005).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Vaupel et al, 2005
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- Authors
- Vaupel, D. B., Tella, S. R., Huso, D. L., Wagner, V. O., Mukhin, A. G., Chefer, S. I., Horti, A. G., London, E. D., Koren, A. O., & Kimes, A. S.
- Affiliations
- National Institutes of Health (US)
- Georgetown University (US)
- BioReliance (United States) (US)
- University of California, Los Angeles (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 312
- Issue
- 1
- Pages
- 355-365
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2171320445
- Cited by
- 28
- References
- 35
- Citations by year
- 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50CA062924, CA062924)
- National Center for Research Resources (RR 000171, K26RR000171)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- α4β2 nicotinic acetylcholine receptor, PET radiotracer, radiopharmaceutical safety, mutagenicity, acute toxicity, convulsant activity, nicotine, electrocardiogram, dosimetry, urinary bladder
- MeSH terms
- Animals, Behavior, Animal, Blood Pressure, Body Temperature, Body Weight, Cardiovascular System, Cerebral Cortex, Convulsants, Dose-Response Relationship, Drug, Electrocardiography, Female, Fluorine Radioisotopes, Heart Rate, Male, Motor Activity, Myocardial Contraction, Primates, Pyridines, Receptors, Nicotinic, Rats, Sprague-Dawley, Positron-Emission Tomography, Mice, Rats
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