title: Synthesis and biological evaluation of novel 4-benzylpiperazine ligands for sigma-1 receptor imaging.
abstract: We report the synthesis and evaluation of 4-benzylpiperazine ligands (BP-CH(3), BP-F, BP-Br, BP-I, and BP-NO(2)) as potential σ(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 σ(1) receptors (K(i)=0.43-0.91nM) and high subtype selectivity (σ(2) receptor: K(i)=40-61nM; K(i)σ(2)/K(i)σ(1)=52-94). [(125)I]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 logD value of [(125)I]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 σ(1) receptors, including the brain, lung, kidney, heart, and spleen. Administration of haloperidol 5min prior to injection of [(125)I]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 [(125)I]BP-I is relatively stable to in vivo deiodination. These findings suggest that the binding of [(125)I]BP-I to σ(1) receptors in vivo is specific.
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
authors.forename: Zi-Jing
authors.initials: ZJ
authors.lastname: Li
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Ren
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Cui
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.forename: Rui-Kun
authors.initials: RK
authors.lastname: Tang
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Bo-Li
authors.initials: BL
authors.lastname: Liu
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Jia
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008813:Mice, Inbred ICR; D008968:Molecular Conformation; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution; D014220:Trialkyltin Compounds / Q000737:chemistry; D000097605:Sigma-1 Receptor
chemical_list: D006220:Haloperidol; D008024:Ligands; D000077489:Piperazine; D010879:Piperazines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D014220:Trialkyltin Compounds; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor; C011559:tributyltin