1 research outputs found
1‑(4‑[<sup>18</sup>F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ<sub>1</sub> Receptors in the Brain
We have designed and synthesized
novel piperazine compounds with
low lipophilicity as σ<sub>1</sub> receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)Âmethyl]Âpiperazine
(<b>10</b>) possessed a low nanomolar σ<sub>1</sub> receptor
affinity and a high selectivity toward the vesicular acetylcholine
transporter (>2000-fold), σ<sub>2</sub> receptors (52-fold),
and adenosine A<sub>2A</sub>, adrenergic α<sub>2</sub>, cannabinoid
CB<sub>1</sub>, dopamine D<sub>1</sub>, D<sub>2L</sub>, γ-aminobutyric
acid A (GABA<sub>A</sub>), NMDA, melatonin MT<sub>1</sub>, MT<sub>2</sub>, and serotonin 5-HT<sub>1</sub> receptors. The corresponding
radiotracer [<sup>18</sup>F]<b>10</b> demonstrated high brain
uptake and extremely high brain-to-blood ratios in biodistribution
studies in mice. Pretreatment with the selective σ<sub>1</sub> receptor agonist SA4503 significantly reduced the level of accumulation
of the radiotracer in the brain. No radiometabolite of [<sup>18</sup>F]<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 [<sup>18</sup>F]<b>10</b> to
σ<sub>1</sub> receptors in rat brain. <i>Ex vivo</i> autoradiography showed a reduced level of binding of [<sup>18</sup>F]<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 σ<sub>1</sub> receptors in Alzheimer’s disease