jm100639f_si_001.pdf (41.17 kB)

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

Download (41.17 kB)
journal contribution
posted on 26.08.2010, 00:00 by Iman A. Moussa, Samuel D. Banister, Corinne Beinat, Nicolas Giboureau, Aaron J. Reynolds, Michael Kassiou
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 1113 and 2536 revealed several highly potent and σ1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N′-(4′-methoxybenzyl)piperazine (13, Ki = 2.7 nM, σ21 = 38) and N-(benzofuran-2-ylmethyl)-N′-(4′-(2′′-fluoroethoxy)benzyl)piperazine (30, Ki = 2.6 nM, σ21 = 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.