Synthesis of 11C-labelled bis(phenylalkyl)amines and their in vitro and in vivo binding properties in rodent and monkey brains.

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.