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

We have designed and synthesized novel piperazine compounds with low lipophilicity as σ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ receptors (52-fold), and adenosine A, adrenergic α, cannabinoid CB, dopamine D, D, γ-aminobutyric acid A (GABA), NMDA, melatonin MT, MT, and serotonin 5-HT receptors. The corresponding radiotracer [F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [F]10 to σ receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ receptors in Alzheimer's disease.