SYNTHESIS AND PRELIMINARY EVALUATION OF [I-123] -4-[[(TRANS-IODOPROPEN-2-YL)OXY]-METHYL]PIPERIDINE - A NOVEL HIGH-AFFINITY SIGMA-RECEPTOR RADIOLIGAND FOR SPECT

)-4-[[(trans-iodopropen-2-yl)oxy]methyl]piperidine ((2) under bar) has been synthesized as a novel iodinated ligand for sigma receptors. Thi s new compound exhibited high affinity (K-i = 0.38 nM) for the sigma-1 receptor and selectivity for sigma-1 vs, sigma-2 receptors (K-i sigma -1/sigma 0-2 = 0.02) using in vitro receptor binding assays, Moderate affinity for muscarinic M(1) (K-1 = 322 nM) and M(2) (K-1 = 1.78 nM) r eceptors and low affinity (K-i = 1,460 nM) for dopamine D-2, receptors was also noted. The lipophilicity of 2 (log P-7.5 = 3.24) is moderate , indicating that the ligand should readily cross the blood/brain barr ier. The corresponding radioiodinated ligand,123I-(2) under bar, was s ynthesized from the appropriate trans vinyl tributylstan-nane precurso r under acidic conditions using oxidative iododestannylation methods. HPLC purification provided the radioligand in yields ranging between 6 3 and 75% EOS (n = 5) and with > 99% radiochemical purity and a specif ic activity > 77,000 MBq/mu mol. Preliminary in vivo distribution and pharmacological blocking studies using I-123-2 were performed in male Australian Albino Wistar rats. I-123-(2) under bar exhibited good brai n uptake (1.11 +/- 0.14 %ID at 20 min PI) with no significant loss of radioactivity from the brain over the course of the study (4 h). The g ross regional brain distribution of the radioligand showed highest upt ake in the posterior cortex and frontal cortex, with slightly lower up take in other brain regions examined. Most of the uptake of radioactiv ity in the brain, lung, heart, muscle, and kidney was prevented by pre -administration of compounds with affinity for sigma receptors, indica ting the in vivo specificity of the ligand. In view of these results, I-123-(2) under bar shows promise for the in vivo tomographic evaluati on of sigma receptor densities. Copyright (C) 1997 Elsevier Science In c.