Department of Psychiatry, Columbia University, New York, New York, USA.
J Nucl Med. 2011 Jul;52(7):1150-5. doi: 10.2967/jnumed.110.084525. Epub 2011 Jun 16.
SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy.
Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events.
Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported.
At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about indication, dose, and therapeutic potential.
在 SEP-225289 的开发过程中进行一项开放标签的 PET 研究，以研究其对多巴胺和 5-羟色胺转运体的占有率。
在 3 个队列中分别给 7 例健康志愿者单次给予不同剂量的 SEP-225289：8mg（n=7）、12mg（n=5）和 16mg（n=7）。在口服 SEP-225289 后大约 24h 进行 PET，以评估在谷水平时的占有率。使用（11）C-N-（3-碘丙-2E-烯基）-2β-羧甲氧基-3β-（4-甲基苯基）去甲托烷（（11）C-PE2I）和（11）C-N，N-二甲基-2-（2-氨基-4-氰基苯硫基）苄胺（（11）C-DASB），分别从 PET 估计多巴胺和 5-羟色胺转运体占有率。在配体注射前评估 SEP-225289 的血浆浓度，并监测不良事件。
随着 SEP-225289 剂量的增加，平均多巴胺和 5-羟色胺转运体占有率增加。8mg 时，平均多巴胺和 5-羟色胺转运体占有率分别为 33%±11%和 2%±13%；12mg 时，分别为 44%±4%和 9%±10%；16mg 时，分别为 49%±7%和 14%±15%。基于占有率与血浆浓度的关系，确定了多巴胺转运体 IC50（50%占有率时的药物血浆浓度）（4.5ng/ml），并推断了最大多巴胺转运体占有率（85%）；然而，低 5-羟色胺转运体占有率使得无法进行类似的 5-羟色胺转运体计算。未报告严重不良事件。
在评估的剂量下，尽管体外效力相似，但多巴胺转运体的占有率明显高于 5-羟色胺转运体，这证实了除了体外测定外，PET 占有率研究可以通过提供关于适应证、剂量和治疗潜力的早期决策，为药物开发过程提供帮助。
