磷酸二酯酶10A正电子发射断层显像剂[(11)C]MK-8193的临床前特性研究
Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [(11)C]MK-8193.
作者信息
Hostetler Eric D, Fan Hong, Joshi Aniket D, Zeng Zhizhen, Eng Waisi, Gantert Liza, Holahan Marie, Meng Xianjun, Miller Patricia, O'Malley Stacey, Purcell Mona, Riffel Kerry, Salinas Cristian, Williams Mangay, Ma Bennett, Buist Nicole, Smith Sean M, Coleman Paul J, Cox Christopher D, Flores Brock A, Raheem Izzat T, Cook Jacquelynn J, Evelhoch Jeffrey L
机构信息
Imaging, Merck & Co., Inc, West Point, PA, USA.
Drug Metabolism, Merck & Co., Inc, West Point, PA, USA.
出版信息
Mol Imaging Biol. 2016 Aug;18(4):579-87. doi: 10.1007/s11307-015-0910-0.
PURPOSE
A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [(11)C]MK-8193 is described.
PROCEDURES
In vitro binding studies with [(3)H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [(11)C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor.
RESULTS
[(3)H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [(11)C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships.
CONCLUSIONS
[(11)C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [(11)C]MK-8193 in humans is warranted.
目的
一种用于磷酸二酯酶10A（PDE10A）的正电子发射断层扫描（PET）示踪剂对于指导发现和开发作为潜在治疗药物的PDE10A抑制剂是很有必要的。本文描述了PDE10A PET示踪剂[(11)C]MK-8193的临床前特征。
程序
用[(3)H]MK-8193在大鼠、猴子和人类脑组织中进行体外结合研究。用[(11)C]MK-8193在大鼠和恒河猴身上进行PET研究，分别在基线期以及给予PDE10A抑制剂之后。
结果
[(3)H]MK-8193在大鼠、猴子和人类脑组织中是一种高亲和力、选择性的PDE10A放射性配体。在体内，[(11)C]MK-8193显示出快速动力学、低重测变异性以及一个被结构多样的PDE10A抑制剂取代的大的特异性信号，从而能够确定药代动力学/酶占有率关系。
结论
[(11)C]MK-8193是一种用于在大鼠和猴子身上对PDE10A治疗候选药物进行临床前特征描述的有用PET示踪剂。有必要对[(11)C]MK-8193在人类中的情况进行进一步评估。
Zotero 插件