Abstract
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.
Footnotes
- Received September 29, 1999.
- Accepted December 10, 1999.
-
Send reprint requests to: Edythe D. London, Brain Imaging Center, National Institute on Drug Abuse, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: elondon{at}tracer.org
-
↵1 A preliminary report of this work has been presented previously (Mukhin AG, Gündisch D, Horti AG, Koren AO, Kimes AS, Vaupel DB and London ED (1998) 5-Iodo-A-85380–a novel highly selective ligand for the α4β2 subtype of nicotinic acetylcholine receptors.Soc Neurosci Abstr 24:85).
-
The research described in this publication was supported by the Intramural Research Program of the National Institute on Drug Abuse, funding from the Office of the National Drug Control Policy, and funding from Department of Veterans Affairs (Connecticut/Massachusetts VA Mental Illness Research, Education, and Clinical Center). Samples of postmortem brain tissue were obtained from the Brain and Tissue Bank for Developmental Disorders under National Institutes of Health Contract no. NO1-HD-1–3138.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
Log in using your username and password
Purchase access
In this issue
5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors
