title: NIDA522131, a new radioligand for imaging extrathalamic nicotinic acetylcholine receptors: in vitro and in vivo evaluation.
abstract: A novel radioligand, 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine (NIDA522131), for imaging extrathalamic nicotinic acetylcholine receptors (nAChRs) was characterized in vitro and in vivo using positron emission tomography. The K(d) and T(1/2) of dissociation of NIDA522131 binding measured at 37 degrees C in vitro were 4.9 +/- 0.4 pmol/L and 81 +/- 5 min, respectively. The patterns of radioactivity distribution in monkey brain in vivo was similar to that of 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2FA), a radioligand that has been successfully used in humans, and matched the alpha(4)beta(2)* nAChRs distribution. Comparison between [(18)F]NIDA522131 and 2FA demonstrated better in vivo binding properties of the new radioligand and substantially greater radioactivity accumulation in brain. Consistent with [(18)F]NIDA522131 elevated affinity for nAChRs and its increased lipophilicity, both, the total and non-displaceable distribution volumes were substantially higher than those of 2FA. Estimated binding potential values in different brain regions, characterizing the specificity of receptor binding, were 3-4 fold higher for [(18)F]NIDA522131 than those of 2FA. Pharmacological evaluation in mice demonstrated a toxicity that was comparable to 2FA and is in agreement with a 2300 fold higher affinity at alpha(4)beta(2)* versus alpha(3)beta(4)* nAChRs. These results suggest that [(18)F]NIDA522131 is a promising positron emission tomography radioligand for studying extrathalamic nAChR in humans.
authors.affiliation: Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, Department of Health and Human Services, Baltimore, Maryland, USA.
authors.forename: Svetlana I
authors.initials: SI
authors.lastname: Chefer
authors.forename: Olga A
authors.initials: OA
authors.lastname: Pavlova
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: D Bruce
authors.initials: DB
authors.lastname: Vaupel
authors.forename: Alane S
authors.initials: AS
authors.lastname: Kimes
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.forename: Elliot
authors.initials: E
authors.lastname: Stein
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Mukhin
mesh_terms: D000818:Animals; D001345:Autoradiography; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010949:Plasma / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013788:Thalamus / Q000000981:diagnostic imaging*
chemical_list: C486789:6-chloro-3-((2-azetidinyl)methoxy)-5-(2-fluoropyridin-5-yl)pyridine; D001384:Azetidines; D005462:Fluorine Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic