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 piperazine compounds with low lipophilicity as σ 1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine ( 10 ) possessed a low nanomolar σ 1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ 2 receptors (52-fold), and adenosine A 2A, adrenergic α 2, cannabinoid CB 1, dopamine D 1, D 2L, γ-aminobutyric acid A (GABA A ), NMDA, melatonin MT 1, MT 2, and serotonin 5-HT 1 receptors. The corresponding radiotracer [ 18 F] 10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ 1 receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [ 18 F] 10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [ 18 F] 10 to σ 1 receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [ 18 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 1 receptors in Alzheimer’s disease.