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

The Journal of Pharmacology and Experimental Therapeutics
D Bruce VaupelAlane S Kimes

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 critica...Continue Reading

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Citations

Jul 28, 2010·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Irina EsterlisJulie K Staley
May 24, 2007·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Jean-Dominique GallezotMarie-Claude Grégoire
Oct 31, 2006·Biological Psychiatry·George Bartzokis
Apr 30, 2013·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jill R TurnerJulie A Blendy
Jan 30, 2008·European Journal of Nuclear Medicine and Molecular Imaging·Osama SabriPeter Brust
Jul 4, 2006·Brain : a Journal of Neurology·F PicardM Bottlaender
Aug 27, 2016·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Hiroto KuwabaraAndrew G Horti

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