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

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Two new ¹¹C-labelled ligands, N-(3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenyl)propylamine ([¹¹C]2) and N-(3-(4-hydroxyphenyl)butyl)-3-(4-methoxyphenyl)butylamine ([¹¹C]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 [¹¹C]methyl iodide was readily accomplished. The in vitro inhibition experiments using rat brain slices showed that [¹¹C]2 and [¹¹C]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 Zn²⁺ produced significant inhibition of both [¹¹C]2 and [¹¹C]3 bindings. Intravenous injection of [¹¹C]3 in mice showed almost homogenous distribution throughout the brain. Attempts to block the tracer uptake of [¹¹C]3 by pre-injection with the unlabelled 3 or spermine in rats were unsuccessful, but a small decrease in the cerebral uptake of [¹¹C]3 by co-treatment with the unlabelled 3 was observed in a monkey PET study. The present findings indicate that none of these ¹¹C-labelled analogues have potential for PET study of binding sites on the N-methly-D-aspartate (NMDA) receptors.