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

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 11−13and 25−36revealed several highly potent and σ1selective ligands, notably, N-(benzofuran-2-ylmethyl)-N′-(4′-methoxybenzyl)piperazine (13, Ki= 2.7 nM, σ2/σ1= 38) and N-(benzofuran-2-ylmethyl)-N′-(4′-(2′′-fluoroethoxy)benzyl)piperazine (30, Ki= 2.6 nM, σ2/σ1= 187). Structural features for optimal σ1receptor affinity and selectivity over the σ2receptor were identified. On the basis of its favorable log Dvalue, 13was selected as a candidate for the development of a σ1receptor positron emission tomography radiotracer. [11C]13showed high uptake in the brain and other σ receptor-rich organs of a Papio hamadryasbaboon. The in vivo evaluation of [11C]13indicates that this radiotracer is a suitable candidate for imaging the σ1receptor in neurodegenerative processes. [ABSTRACT FROM AUTHOR]