Synthesis and biological evaluation of novel 4-benzylpiperazine ligands for sigma-1 receptor imaging

We report the synthesis and evaluation of 4-benzylpiperazine ligands (BP-CH3, BP-F, BP-Br, BP-I, and BP-NO2) as potential sigma(1) receptor ligands. The X-ray crystal structure of BP-Br, which crystallized with monoclinic space group P2(1)/c, has been determined. In vitro competition binding assays showed that all the five ligands exhibit low nanomolar affinity for sigma(1) receptors (K-i = 0.43-0.91 nM) and high subtype selectivity (sigma(2) receptor: K-i = 40-61 nM; K-i sigma(2)/K-i sigma(1) = 52-94). [I-125] BP-I (1-(1,3-benzodioxol-5-ylmethyl)-4-(4-iodobenzyl) piperazine) was prepared in 53 +/- 10% isolated radiochemical yield, with radiochemical purity of > 99% by HPLC analysis after purification, via iododestannylation of the corresponding tributyltin precursor. The log D value of [I-125] BP-I was found to be 2.98 +/- 0.17, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiolabeled substances in organs known to contain sigma(1) receptors, including the brain, lung, kidney, heart, and spleen. Administration of haloperidol 5 min prior to injection of [I-125] BP-I significantly reduced the concentration of radioactivity in the above-mentioned organs. The accumulation of radiolabeled substance in the thyroid was quite low suggesting that [I-125] BP-I is relatively stable to in vivo deiodination. These findings suggest that the binding of [I-125] BP-I to sigma(1) receptors in vivo is specific. (C) 2011 Elsevier Ltd. All rights reserved.