[18F]FBFP

We report a convenient radiosynthesis and the first positron emission tomography (PET) imaging evaluation of [¹⁸F]FBFP as a potent sigma-1 (σ₁) receptor radioligand with advantageous characteristics. [¹⁸F]FBFP was synthesized in one step from an iodonium ylide precursor. In cynomolgus monkeys, [¹⁸F]FBFP displayed high brain uptake and suitable tissue kinetics for quantitative analysis. It exhibited heterogeneous distribution with higher regional volume of distribution (V_T) values in the amygdala, hippocampus, insula, and frontal cortex. Pretreatment with the σ₁ receptor agonist SA4503 (0.5 mg/kg) significantly reduced radioligand uptake in the monkey brain (>95%), indicating high binding specificity of [¹⁸F]FBFP in vivo. Compared with (S)-[¹⁸F]fluspidine, [¹⁸F]FBFP possessed higher regional nondisplaceable binding potential (BP_ND) values across the brain regions. These findings demonstrate that [¹⁸F]FBFP is a highly promising PET radioligand for imaging and quantification of σ₁ receptors in humans.

We have designed and synthesized novel piperazine compounds with low lipophilicity as σ₁ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) 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]10 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]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [¹⁸F]10 to σ₁ receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [¹⁸F]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 σ₁ receptors in Alzheimer's disease.