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Vol. 57, Issue 3, 642-649, March 2000
4
2 Subtype-Selective Ligand for
Nicotinic Acetylcholine Receptors1
Brain Imaging Center, Intramural Research Program, National
Institute on Drug Abuse, Baltimore, Maryland (A.G.M., D.G., A.G.H.,
A.O.K., A.S.K., J.C., D.B.V., E.D.L.) and Department of Psychiatry,
Yale University School of Medicine, New Haven, Connecticut (G.T.,
S.L.K., M.R.P., R.B.I.)
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 and
123I. Here we present the results of experiments
characterizing this radioiodinated ligand in vitro. The affinity of
5-[125I]iodo-A-85380 for 
4
2 nAChRs in rat and human
brain is defined by Kd 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 42 subtype than to other nAChR subtypes. In rat adrenal
glands, 5-iodo-A-85380 binds to nAChRs containing 3 and 4
subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th
and 1/190th the affinity of epibatidine at 7 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 2 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
(t1/2 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 42 nAChRs, respectively.
42 subtype of nicotinic acetylcholine receptors. Soc Neurosci Abstr 24:85).
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