Pharmacological evaluation of [11C]A-84543: An enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors

Michael Kassiou, Ursula A. Scheffel, Hayden T. Ravert, William B. Mathews, John L. Musachio, Edythe D. London, Robert F. Dannals

Research output: Contribution to journalArticlepeer-review

Abstract

[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-HT(2c)), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D2/δ) 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.

Original languageEnglish (US)
Pages (from-to)PL13-PL18
JournalLife Sciences
Volume63
Issue number1
DOIs
StatePublished - May 29 1998

Keywords

  • Brain
  • Enantiomer
  • []A-84543
  • nAChR radiotracer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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