Design, Synthesis, and Structure−Affinity Relationships of Regioisomeric N-Benzyl Alkyl Ether Piperazine Derivatives as σ-1 Receptor Ligands

• Published in: Journal of medicinal chemistry 2010-08, Vol.53 (16), p.6228-6239
• Main Authors: Moussa, Iman A, Banister, Samuel D, Beinat, Corinne, Giboureau, Nicolas, Reynolds, Aaron J, Kassiou, Michael
• Format: Article
• Language: English
• Subjects: Animals; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacokinetics; Binding, Competitive; Brain - metabolism; Carbon Radioisotopes; Ethers - chemical synthesis; Ethers - chemistry; Ethers - pharmacokinetics; In Vitro Techniques; Ligands; Papio; PC12 Cells; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacokinetics; Positron-Emission Tomography; Radioligand Assay; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rats; Receptors, sigma - metabolism; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100639f

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 σ1 {[3H](+)-pentazocine} and σ2 ([3H]DTG) receptor binding profiles of piperazines 11−13 and 25−36 revealed several highly potent and σ1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N′-(4′-methoxybenzyl)piperazine (13, K i = 2.7 nM, σ2/σ1 = 38) and N-(benzofuran-2-ylmethyl)-N′-(4′-(2′′-fluoroethoxy)benzyl)piperazine (30, K i = 2.6 nM, σ2/σ1 = 187). Structural features for optimal σ1 receptor affinity and selectivity over the σ2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a σ1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other σ 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 σ1 receptor in neurodegenerative processes.