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 σ₁ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)­methyl]­piperazine (<b>10</b>) possessed a low nanomolar σ₁ receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ₂ receptors (52-fold), and adenosine A_2A, adrenergic α₂, cannabinoid CB₁, dopamine D₁, D_2L, γ-aminobutyric acid A (GABA_A), NMDA, melatonin MT₁, MT₂, and serotonin 5-HT₁ receptors. The corresponding radiotracer [¹⁸F]<b>10</b> demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ₁ receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [¹⁸F]<b>10</b> was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [¹⁸F]<b>10</b> to σ₁ receptors in rat brain. <i>Ex vivo</i> autoradiography showed a reduced level of binding of [¹⁸F]<b>10</b> 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 σ₁ receptors in Alzheimer’s disease