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

Biol Pharm Bull. 2004 Apr;27(4):531-7. doi: 10.1248/bpb.27.531.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis
  • Amines / pharmacokinetics
  • Amines / pharmacology*
  • Animals
  • Binding Sites
  • Brain / drug effects*
  • Brain / metabolism
  • Butylamines / chemical synthesis
  • Butylamines / pharmacokinetics
  • Butylamines / pharmacology*
  • Carbon Radioisotopes
  • In Vitro Techniques
  • Injections, Intravenous
  • Isotope Labeling
  • Macaca mulatta
  • Male
  • Mice
  • Piperidines / pharmacology
  • Propylamines / chemical synthesis
  • Propylamines / pharmacokinetics
  • Propylamines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spermine / pharmacology
  • Tissue Distribution

Substances

  • Amines
  • Butylamines
  • Carbon Radioisotopes
  • N-(3-(4-hydroxyphenyl)butyl)-3-(4-methoxyphenyl)butylamine
  • N-(3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenyl)propylamine
  • NMDA receptor A1
  • NR2B NMDA receptor
  • Piperidines
  • Propylamines
  • Receptors, N-Methyl-D-Aspartate
  • Spermine
  • traxoprodil mesylate
  • ifenprodil