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5-Iodo-A-85380, an a4ß2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

journal contribution
posted on 2023-06-07, 17:48 authored by Alexey G Mukhin, Daniela Gündisch, Andrew G Horti, Andrei O Koren, Gilles Tamagnan, Alane S Kimes, Joann Chambers, D Bruce Vaupel, Sarah KingSarah King, Marina R Picciotto, Robert B Innis, Edythe D London
In an effort to develop selective radioligands for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs), we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with 125I and123I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[125I]iodo-A-85380 for a4ß2 nAChRs in rat and human brain is defined by K d values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the a4ß2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing a3 and ß4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at a7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[125I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the ß2 subunit of nAChRs. Binding of 5-[125I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor–ligand complex (t 1/2 for dissociation ~2 h). These properties, along with other features observed previously in in vivo experiments (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with 125I or 123I, is superior to other radioligands available for in vitro and in vivo studies of a4ß2 nAChRs, respectively.

History

Publication status

  • Published

Journal

Molecular Pharmacology

ISSN

0026-895X

Publisher

American Society for Pharmacology and Experimental Therapeutics

Issue

3

Volume

57

Page range

642-649

Department affiliated with

  • Psychology Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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