Synthesis of ^<11>C-Labelled Bis (phenylalkyl) amines and Their in Vitro and in Vivo Binding Properties in Rodent and Monkey Brains (Medicinal Chemistry)

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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 homogenous 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-methly-D-aspartate (NMDA) receptors.
社団法人日本薬学会の論文
2004-04-01