1-(4-[18F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ1 Receptors in the Brain

We have designed and synthesized novel piperatine compounds with low lipophilicity as sigma(1) receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar sigma(1) receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>20004-fold), sigma(2) receptors (52-fOld), and adenosine A(2A), adrenergic alpha(2), cannabinoid CBI, dopamine D-1, D-2L, gamma-amitiobutyric acid A (GABA(A)), NMDA, melatonin MT1, MT2, and Serntonin 5-HT1 receptors. The corresponding radiotracer [F-18]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective sigma(1) receptor agonist SA4503- significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [F-18]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high, specific binding of [F-18]10 to sigma(1) receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [F-18]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mite, indicating the potential dysfunction of sigma(1) receptors in Alzheimer's disease.