Pharmacological evaluation of [11C]A-84543: an enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors.
[11C]A-84543, 3-[(1-[11C]methyl-2(S)-pyrrolidinyl)methoxy]pyridine, is a specific and enantioselective neuronal nicotinic acetylcholine receptor (nAChR) radiotracer. The in vivo biodistribution of this radiotracer 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 hippocampus (7.6 %ID/g) at 5 min followed by clearance. As a measure of specificity, the thalamus/cerebellar ratio reached a maximum of 2.3 at 30 min post-injection. Radioactivity in the thalamus and superior colliculus was reduced by 33% by pre-administration of unlabeled A-84543. The nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced the radioactivity due to [11C]A-84543 in the superior colliculus by 41%, 38%, and 27%, respectively, while lobeline, which also interacts with central nAChRs, produced a 24% inhibition. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect on [11C]A-84543 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D2/sigma) also displayed no inhibitory effect in any brain region studied. With the pharmacologically less active enantiomer, 3-[(1-[11C]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. [11C]A-84543 displays enantioselectivity for nAChRs and may deserve further investigation as a possible PET radiotracer.
Brain Imaging Section, Division of Intramural Research, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
M
M
Kassiou
U A
UA
Scheffel
H T
HT
Ravert
W B
WB
Mathews
J L
JL
Musachio
E D
ED
London
R F
RF
Dannals
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D008024:Ligands; D011759:Pyrrolidines; D011978:Receptors, Nicotinic