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

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.