Chen Laigao, Nabulsi Nabeel, Naganawa Mika, Zasadny Kenneth, Skaddan Marc B, Zhang Lei, Najafzadeh Soheila, Lin Shu-Fei, Helal Christopher J, Boyden Tracey L, Chang Cheng, Ropchan Jim, Carson Richard E, Villalobos Anabella, Huang Yiyun
Pfizer Worldwide Research and Development, Groton, Connecticut; and.
PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
J Nucl Med. 2016 Sep;57(9):1448-53. doi: 10.2967/jnumed.115.171454. Epub 2016 May 19.
The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-05270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates.
(18)F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and PET imaging in nonhuman primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data.
(18)F-PF-05270430 was synthesized in greater than 98% radiochemical purity and high specific activity. In the nonhuman primate brain, uptake of (18)F-PF-05270430 was fast, with peak concentration (SUVs of 1.5-1.8 in rhesus monkeys) achieved within 7 min after injection. The rank order of uptake was striatum > neocortical regions > cerebellum. Regional time-activity curves were well fitted by the 2-tissue-compartment model and the multilinear analysis-1 (MA1) method to arrive at reliable estimates of regional distribution volume (VT) and binding potential (BPND) with 120 min of scan data. Regional VT values (MA1) ranged from 1.28 mL/cm(3) in the cerebellum to 3.71 mL/cm(3) in the putamen, with a BPND of 0.25 in the temporal cortex and 1.92 in the putamen. Regional BPND values estimated by the simplified reference tissue model (SRTM) were similar to those from MA1. Test-retest variability in high-binding regions (striatum) was 4% ± 6% for MA1 VT, 13% ± 6% for MA1 BPND, and 13% ± 7% SRTM BPND, respectively. Pretreatment of animals with the PDE2A inhibitor PF-05180999 resulted in a dose-dependent reduction of (18)F-PF-05270430 specific binding, with a half maximal effective concentration of 69.4 ng/mL in plasma PF-05180999 concentration.
(18)F-PF-05270430 displayed fast and reversible kinetics in nonhuman primates, as well as specific binding blockable by a PDE2A inhibitor. This is the first PET tracer with desirable imaging properties and demonstrated ability to image and quantify PDE2A in vivo.
磷酸二酯酶2A（PF - 05270430）是开发用于治疗认知障碍的新型治疗药物的潜在靶点。本研究的目的是在非人灵长类动物中评估PDE2A配体（18）F - PF - 05270430，即4 - （3 - 氟氮杂环丁烷 - 1 - 基） - 7 - 甲基 - 5 - （1 - 甲基 - 5 - （4 - （三氟甲基）苯基） - 1H - 吡唑 - 4 - 基）咪唑并[1,5 - f][1,2,4]三嗪。
（18）F - PF - 05270430通过两种方法经其甲苯磺酸盐前体的亲核取代进行放射性标记。在啮齿动物中进行组织代谢物分析，并在基线和阻断条件下对非人灵长类动物进行PET成像，以确定新放射性配体的药代动力学和结合特性。评估了各种动力学建模方法，以选择分析成像数据的最佳方法。
（18）F - PF - 05270430以大于98％的放射化学纯度和高比活度合成。在非人灵长类动物脑中，（18）F - PF - 05270430的摄取迅速，注射后7分钟内达到峰值浓度（恒河猴的SUV为1.5 - 1.8）。摄取的顺序为纹状体>新皮质区域>小脑。区域时间 - 活性曲线通过双组织室模型和多线性分析 - 1（MA1）方法得到很好的拟合，利用扫描120分钟的数据得出区域分布容积（VT）和结合潜能（BPND）的可靠估计值。区域VT值（MA1）范围从小脑的1.28 mL/cm³到壳核的3.71 mL/cm³，颞叶皮质的BPND为0.25，壳核的BPND为1.92。简化参考组织模型（SRTM）估计的区域BPND值与MA1的相似。高结合区域（纹状体）的重测变异性，MA1 VT为4％±6％，MA1 BPND为13％±6％，SRTM BPND为13％±7％。用PDE2A抑制剂PF - 05180999对动物进行预处理导致（18）F - PF - 05270430特异性结合呈剂量依赖性降低，血浆PF - 05180999浓度的半数最大有效浓度为69.4 ng/mL。
（18）F - PF - 05270430在非人灵长类动物中表现出快速且可逆的动力学，以及可被PDE2A抑制剂阻断的特异性结合。这是首个具有理想成像特性并证明能够在体内对PDE2A进行成像和定量的PET示踪剂。
