Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Advanced Institutes of Convergence Technology, Suwon, South Korea.
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
Urology. 2014 Jul;84(1):245.e1-7. doi: 10.1016/j.urology.2014.03.014. Epub 2014 May 10.
To investigate the efficacy of DA-8031, a novel compound for the treatment of premature ejaculation, we measured serotonin transporter (SERT) occupancy by DA-8031, as well as DA-8031-induced changes in extracellular serotonin levels, in the rat brain using positron emission tomography (PET) and 11C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([11C]DASB) and in vivo microdialysis, respectively.
[11C]DASB PET scans were performed in rats with graded doses of DA-8031 (vehicle: 10, 30, and 100 mg/kg). SERT occupancy in the midbrain was determined using binding potentials for [11C]DASB calculated by the multilinear reference tissue model. Extracellular serotonin levels were monitored in the dorsal raphe nucleus of rats after the administration of DA-8031 (10-100 mg/kg) using in vivo microdialysis.
PET data indicated a reduction of [11C]DASB binding to SERTs in the midbrain as a function of DA-8031 dose. SERT occupancy for each DA-8031 dose (10-100 mg/kg) ranged between 31% and 84%. The drug dose required for 50% occupancy of SERT was 13.5 mg/kg in the midbrain, comparable with previous preclinical behavioral data (∼10-30 mg/kg). In vivo microdialysis showed that DA-8031 produced a dose-dependent increase in extracellular serotonin levels in the dorsal raphe nucleus (33%-81% increase for doses of 10-100 mg/kg).
These preclinical data provide a proof of mechanism for DA-8031 as a novel compound of targeting the SERT for the treatment of premature ejaculation, warranting further clinical trials. They also offer insight into the optimal drug dose needed to exert therapeutic effects while minimizing adverse effects in humans.
为了研究新型化合物 DA-8031 治疗早泄的疗效，我们通过正电子发射断层扫描（PET）和 11C-N,N-二甲基-2-（2-氨基-4-氰基苯硫基）苄胺（[11C]DASB），分别测量了 DA-8031 对大鼠脑内 5-羟色胺转运体（SERT）占有率，以及 DA-8031 诱导的细胞外 5-羟色胺水平变化。
在给予不同剂量 DA-8031（载体：10、30 和 100 mg/kg）的大鼠中进行 [11C]DASB PET 扫描。通过多线性参比组织模型计算 [11C]DASB 的结合势来确定中脑 SERT 的占有率。使用在体微透析法在大鼠给予 DA-8031（10-100 mg/kg）后监测背缝核细胞外 5-羟色胺水平。
PET 数据表明，随着 DA-8031 剂量的增加，[11C]DASB 与 SERT 结合减少。每个 DA-8031 剂量（10-100 mg/kg）的 SERT 占有率在 31%-84%之间。DA-8031 对 SERT 的 50%占有率所需的药物剂量为 13.5 mg/kg，与之前的临床前行为数据（10-30 mg/kg）相当。在体微透析显示，DA-8031 使背缝核细胞外 5-羟色胺水平呈剂量依赖性增加（10-100 mg/kg 剂量增加 33%-81%）。
这些临床前数据为 DA-8031 作为一种新型化合物，通过靶向 SERT 治疗早泄提供了机制上的证据，值得进一步进行临床试验。这些数据还为在发挥治疗作用的同时，最小化人体不良反应所需的最佳药物剂量提供了深入了解。
