[11C]cyclopropyl-FLB 457: a PET radioligand for low densities of dopamine D2 receptors

Bioorg Med Chem. 2008 Jul 1;16(13):6467-73. doi: 10.1016/j.bmc.2008.05.039. Epub 2008 May 20.

Abstract

(S)-5-bromo-N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide (4) has pico-molar in vitro binding affinity to D(2) receptor (K(i) (D(2))=0.003 nM) with lower affinity to D(3) receptor (K(i) (D(3))=0.22 nM). In this study, we describe radiosynthesis of [(11)C]4 and evaluation of its binding characteristics in post-mortem human brain autoradiography and with PET in cynomolgus monkeys. The (11)C labelled 4 was synthesized by using [(11)C]methyltriflate in a methylation reaction with its phenolic precursor with good incorporation yield (64+/-11%, DCY) and high specific radioactivity >370 GBq/micromol (>10,000 Ci/mmol). In post-mortem human brain autoradiography [(11)C]4 exhibited high specific binding in brain regions enriched with dopamine D(2)/D(3) receptors and low level of non-specific binding. In cynomolgus monkeys [(11)C]4 exhibited high brain uptake reaching 4.4% ID at 7.5 min. The binding in the extrastriatal low density D(2)-receptor regions; thalamus and frontal, parietal, temporal, and occipital cortex, was clearly visible. Pre-treatment with raclopride (1 mg/kg as tartrate) caused high reduction of binding in extrastriatal regions, including cerebellum. [(11)C]4 is a promising radioligand for imaging D(2) receptors in low density regions in brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Isotopes
  • Chromatography, High Pressure Liquid
  • Haplorhini
  • Humans
  • Ligands
  • Molecular Structure
  • Positron-Emission Tomography
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Salicylamides / chemistry*
  • Salicylamides / metabolism*

Substances

  • Carbon Isotopes
  • Ligands
  • Pyrrolidines
  • Receptors, Dopamine D2
  • Salicylamides
  • FLB 457