PHARMACOLOGICAL EVALUATION OF [C-11] A-84543 - AN ENANTIOSELECTIVE LIGAND FOR IN-VIVO STUDIES OF NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS

[C-11]A-84543, (1-[C-11]methyl-2(S)-pyrrolidinyl)methoxy]pyridine is a specific and enantioselective neuronal nicotinic acetylcholine recept or (nAChR) radiotracer. The in vivo biodistribution of this radiotrace r in mice showed high brain uptake and a distribution consistent with the density of nAChRs. Highest uptake was observed in the thalamus (9. 6 %ID/g), cortex (9.9 %ID/g), superior colliculus (7.6 %ID/g) and hipp ocampus (7.6 %ID/g) at 5 min followed by clearance. As a measure of sp ecificity, the thalamus/cerebellar ratio reached a maximum of 2.3 at 3 0 min post-injection. Radioactivity in the thalamus and superior colli culus was reduced by 33% by pre-administration of unlabeled A-84543. T he nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced t he radioactivity due to [C-11]A-84543 in the superior colliculus by 41 %, 38%, and 27%, respectively, while lobeline, which also interacts wi th central nAChRs, produced a 24% inhibition. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect on [C-11]A-84543 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C), scopolami ne (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and hal operidol (D-2/sigma) also displayed no inhibitory effect in any brain region studied. With the pharmacologically less active enantiomer, 3-[ (1-[C-11]methyl-2(R)-pyrrolidinyl)methoxy] pyridine, high brain uptake was also observed, but with a low thalamus/cerebellar ratio of 1.4 at 30 min post-injection. [C-11]A-84543 displays enantioselectivity for nAChRs and may deserve further investigation asa possible PET radiotra cer. (C) 1998 Elsevier Science Inc.