18F-labeled benzamides for studying the dopamine D2 receptor with positron emission tomography

J Med Chem. 1993 Nov 12;36(23):3707-20. doi: 10.1021/jm00075a028.

Abstract

Two series of (N-benzylpiperidin-4-yl)- and (9-azabicyclo[3.3.1]nonan- 3 beta-yl)benzamides were prepared, and in vitro binding assays were used to measure the affinity of these compounds for dopamine D2, dopamine D3, serotonin 5-HT2, and alpha 2-adrenergic receptors. The results of these studies indicated compounds 23, 26b, and 34 have the selectivity needed for in vivo studies of the D2 (and possibly D3) receptors. 18F-Labeled analogues of 23, 26b and 34 were prepared by N-alkylation of the corresponding desbenzyl precursors with [18F]-4-fluorobenzyl iodide. Preliminary in vivo studies demonstrated that [18F]-23 and [18F]-26b are suitable candidates for further evaluation in positron emission tomography imaging studies. The slow rate of washout of [18F]-34 from nondopaminergic regions and its comparatively high lipophilicity indicates that this compound may not be suitable for imaging studies because of a high level of nonspecific binding.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Baculoviridae / genetics
  • Benzamides / chemical synthesis*
  • Benzamides / metabolism
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic*
  • Fluorine Radioisotopes*
  • Molecular Structure
  • Moths
  • Piperidines / chemical synthesis*
  • Piperidines / metabolism
  • Pituitary Neoplasms / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha / metabolism
  • Receptors, Dopamine / genetics
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3
  • Receptors, Serotonin / metabolism
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Tomography, Emission-Computed*
  • Tumor Cells, Cultured

Substances

  • Benzamides
  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Drd3 protein, rat
  • Fluorine Radioisotopes
  • Piperidines
  • Receptors, Adrenergic, alpha
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptors, Serotonin
  • Recombinant Proteins
  • 2,3-dimethoxy-N-(1-(4-fluorobenzyl)piperidin-4-yl)benzamide
  • 2,3-dimethoxy-N-(9-(4-fluorobenzyl)-9-azabicyclo(3.3.1)nonan-3-yl)benzamide