RT Journal Article
SR Electronic
T1 5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 642
OP 649
DO 10.1124/mol.57.3.642
VO 57
IS 3
A1 Alexey G. Mukhin
A1 Daniela Gündisch
A1 Andrew G. Horti
A1 Andrei O. Koren
A1 Gilles Tamagnan
A1 Alane S. Kimes
A1 Joann Chambers
A1 D. Bruce Vaupel
A1 Sarah L. King
A1 Marina R. Picciotto
A1 Robert B. Innis
A1 Edythe D. London
YR 2000
UL http://molpharm.aspetjournals.org/content/57/3/642.abstract
AB 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 α4β2 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 α4β2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing α3 and β4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at α7 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 β2 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 α4β2 nAChRs, respectively.