title: Synthesis of 11C-labelled bis(phenylalkyl)amines and their in vitro and in vivo binding properties in rodent and monkey brains.
abstract: Two new (11)C-labelled ligands, N-(3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenyl)propylamine ([(11)C]2) and N-(3-(4-hydroxyphenyl)butyl)-3-(4-methoxyphenyl)butylamine ([(11)C]3) were designed based on bis(phenylalkyl)amines (1) which have been reported as polyamine site antagonists with high-selectivity for NR1A/2B NMDA receptors, and radiolabelling of the corresponding phenol precursors with [(11)C]methyl iodide was readily accomplished. The in vitro inhibition experiments using rat brain slices showed that [(11)C]2 and [(11)C]3 share the binding sites with spermine and/or ifenprodil but not with CP-101,606, a highly potent NR2B-selective NMDA antagonist, and that divalent cations such as Zn(2+) produced significant inhibition of both [(11)C]2 and [(11)C]3 bindings. Intravenous injection of [(11)C]3 in mice showed almost homogeneous distribution throughout the brain. Attempts to block the tracer uptake of [(11)C]3 by pre-injection with the unlabelled 3 or spermine in rats were unsuccessful, but a small decrease in the cerebral uptake of [(11)C]3 by co-treatment with the unlabelled 3 was observed in a monkey PET study. The present findings indicate that none of these (11)C-labelled analogues have potential for PET study of binding sites on the N-methyl-D-aspartate (NMDA) receptors.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
authors.forename: Fumie
authors.initials: F
authors.lastname: Kurosaki
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002082:Butylamines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011437:Propylamines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013096:Spermine / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000588:Amines; D002082:Butylamines; D002250:Carbon Radioisotopes; D010880:Piperidines; D011437:Propylamines; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; C493502:N-(3-(4-hydroxyphenyl)butyl)-3-(4-methoxyphenyl)butylamine; C493501:N-(3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenyl)propylamine; C121001:NR2B NMDA receptor; C095106:traxoprodil mesylate; C010739:ifenprodil