5-[I-125/123]lodo-3(2(S)-azetidinylmethoxy)pyridine, a radioiodinated analog of A-85380 for in vivo studies of central nicotinic acetylcholine receptors.
The in vivo biodistribution profile of the novel nicotinic acetylcholine receptor (nAChR) radioligand 5-[I-125/123]Iodo-3(2(S)-azetidinylmethoxy)pyridine, [I-125/123]-5-IA, in mouse brain was examined. This radiotracer displayed good brain penetration (3.1% of the injected dose (ID) in whole brain at 15 min post-radioligand injection). Radioligand distribution was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus (14.9 %ID/g at 60 min), moderate uptake in cortex (8.5 %ID/g at 60 min), and lowest uptake in the cerebellum (2.4 %ID/g at 60 min). Pretreatment with several different nAChR agonists (A-85380, (-)-nicotine, cytisine) significantly inhibited [I-125]-5-IA binding in all brain regions studied (P < 0.01) demonstrating the high specificity of the radioligand for nAChRs. Blocking doses of the muscarinic antagonist scopolamine and the non-competitive nAChR channel blocker mecamylamine had no significant effect on radioactive uptake supporting the in vitro selectivity of [I-125]-5-IA for the nAChR component of the cholinergic system. [I-125]-5-IA binding sites were shown to be saturable with unlabeled 5-IA. With a relatively low acute toxicity (LD50 > 3 mg/kg via intravenous injection in mice) and high in vivo specificity and selectivity, 5-IA labeled with the imaging radionuclide I-123 may prove useful for single photon emission computed tomography (SPECT) studies of nAChRs in human subjects.
Musachio
J L
JL
Department of Radiology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. jlmusachio@petscan.nm.jhu.edu
Scheffel
U
U
Finley
P A
PA
Zhan
Y
Y
Mochizuki
T
T
Wagner
H N
HN
Dannals
R F
RF
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001392:Azocines; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011807:Quinolizines; D011877:Radionuclide Imaging; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D014018:Tissue Distribution; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001384:Azetidines; D001392:Azocines; D007457:Iodine Radioisotopes; D008464:Mecamylamine; D018727:Muscarinic Antagonists; D009538:Nicotine; D018733:Nicotinic Antagonists; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012601:Scopolamine; C104288:A 85380; C004712:cytisine; D000093843:Quinolizidine Alkaloids