The development of radiolabeled molecular imaging agents for diagnosing Alzheimer's disease.

我们评估了放射性碘化2-[4-（4-碘苯基）哌啶]环己醇（(+)-[^<125>I]-对碘vesamicol） [(+)-[^<125>I]pIV]的(+)-对映体的潜力，在4-苯基哌啶部分的对位处进行放射性碘化，作为单光子发射计算机断层扫描（SPECT）配体用于定位中枢神经系统中的sigma-1受体。在竞争性抑制研究中，(+)-pIV （Ki=1.3nM）对sigma-1 （σ-1）受体的亲和力比(+)-pentazocine （Ki=19.9nM）或haloperidol （Ki=13.5nM）高10倍以上。（+）-pIV对σ-1受体（Ki=1.3nM）的结合亲和力是σ-2受体（Ki=20.4nM）的16倍左右。（+）- piv （Ki=1262nM）对VAChT的亲和力明显低于(-)-vesamicol （Ki=13.0nM）和(-)- piv。（+）-[^<125>I]pIV对多巴胺、血清素、肾上腺素和乙酰胆碱受体有低亲和力。此外，在饱和结合研究中，(+)-[^<125>I]pIV的Kd为6.96 nM，最大结合位点Bmax为799.3 fmol/mg蛋白质。在体内研究中，大量（约占注射剂量的3%）(+)-[^<125>I]pIV在大鼠脑内积累并延长其滞留时间。（+）-[^<125>I]pIV在大鼠脑内的蓄积通过联合给药sigma配体如戊唑嗪或氟哌啶醇显著减少。静脉注射(+)-[^<125>I]pIV后1小时的大鼠脑离体放射自显像显示在富含sigma-1受体的脑区高度定位。因此，(+)-[^<125>I]pIV在体内的分布被认为与sigma-1受体结合。这些结果表明，放射性碘化(+)-pIV可能在体内，至少在动物体内具有成像sigma-1 （σ-1）受体的潜力。

We evaluated the potential of the (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-[^<125>I]-p-iodovesamicol) [(+)-[^<125>I]pIV], radioiodinated at the para position of the 4-phenylpiperidine moiety, as a single photon emission computed tomography (SPECT) ligand for mapping sigma-1 receptor in the central nervous system.In competitive inhibition studies, (+)-pIV (Ki=1.3nM) had more than 10 times higher affinity to the sigma-1 (σ-1) receptor than (+)-pentazocine (Ki=19.9nM) or haloperidol (Ki=13.5nM) known as sigma ligands. Also, the binding affinity of (+)-pIV to the σ-1 receptor (Ki=1.3nM), was about 16 times higher than the sigma-2 (σ-2) receptor (Ki=20.4nM). (+)-pIV (Ki=1262nM) had a much lower affinity to VAChT than (-)-vesamicol (Ki=13.0nM) or (-)-pIV. (+)-[^<125>I]pIV had low affinity to the dopamine, serotonin, adrenaline and acetylcholine receptors. Furthermore, in a saturation binding study, (+)-[^<125>I]pIV exhibited a Kd of 6.96 nM with a maximum number of binding sites Bmax of 799.3 fmol/mg of protein.In vivo studies, significant amounts (approximately 3% of the injected dose) of (+)-[^<125>I]pIV accumulated in rat brain and its retention was prolonged. The accumulation of (+)-[^<125>I]pIV in the rat brain was significantly reduced by the co-administration of sigma ligands such as pentazocine or haloperidol. Ex vivo autoradiography of the rat brain at 1 hr following i.v. injection of (+)-[^<125>I]pIV showed high localization in brain areas rich in sigma-1 receptor. Thus, the distribution of (+)-[^<125>I]pIV was thought to bind to sigma-1 receptor in vivo. These results suggest that radioiodinated (+)-pIV may have the potential to image sigma-1 (σ-1) receptor in vivo, at least in animals.