title: Design, synthesis, and structure-affinity relationships of regioisomeric N-benzyl alkyl ether piperazine derivatives as sigma-1 receptor ligands.
abstract: A series of N-(benzofuran-2-ylmethyl)-N'-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro sigma1 {[3H]+-pentazocine} and sigma2 ([3H]DTG) receptor binding profiles of piperazines 11-13 and 25-36 revealed several highly potent and sigma1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N'-(4'-methoxybenzyl)piperazine (13, Ki=2.7 nM, sigma2/sigma1=38) and N-(benzofuran-2-ylmethyl)-N'-(4'-(2''-fluoroethoxy)benzyl)piperazine (30, Ki=2.6 nM, sigma2/sigma1=187). Structural features for optimal sigma1 receptor affinity and selectivity over the sigma2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a sigma1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other sigma receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the sigma1 receptor in neurodegenerative processes.
authors.affiliation: School of Chemistry, Discipline of Medical Radiation Sciences, University of Sydney, Sydney, NSW, Australia.
authors.forename: Iman A
authors.initials: IA
authors.lastname: Moussa
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Corinne
authors.initials: C
authors.lastname: Beinat
authors.forename: Nicolas
authors.initials: N
authors.lastname: Giboureau
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Reynolds
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008024:Ligands; D016716:PC12 Cells; D010215:Papio; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001572:Benzofurans; D002250:Carbon Radioisotopes; D004987:Ethers; D008024:Ligands; C552109:N-((benzofuran-2-yl)methyl)-N'-(4'-methoxybenzyl)piperazine; D010879:Piperazines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma