Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

• DOI: 10.2967/jnumed.115.171454
• Publication Date: 2016-05-20T09:52:43Z
• Authors: Laigao Chen; Nabeel Nabulsi; Mika Naganawa; Kenneth Zasadny; Marc B. Skaddan; Lei Zhang; Soheila Najafzadeh; Shu-fei Lin; Christopher J. Helal; Tracey L. Boyden; Cheng Chang; Jim Ropchan; Richard E. Carson; Anabella Villalobos; Yiyun Huang
• Keywords: Radioligand; Binding potential

The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents the treatment cognitive impairments. goal present study was to evaluate PDE2A ligand ¹⁸F-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. <b>Methods:</b>¹⁸F-PF-05270430 radiolabeled by 2 methods via nucleophilic substitution its tosylate precursor. Tissue metabolite analysis rodents and PET imaging primates under baseline blocking conditions were performed determine pharmacokinetic binding characteristics new radioligand. Various kinetic modeling approaches assessed select optimal method data. <b>Results:</b>¹⁸F-PF-05270430 synthesized greater than 98% radiochemical purity high specific activity. In primate brain, uptake ¹⁸F-PF-05270430 fast, with peak concentration (SUVs 1.5–1.8 rhesus monkeys) achieved within 7 min after injection. rank order striatum &gt; neocortical regions cerebellum. Regional time–activity curves well fitted 2-tissue-compartment model multilinear analysis-1 (MA1) arrive at reliable estimates regional distribution volume (<i>V</i>_T) (<i>BP</i>_ND) 120 scan <i>V</i>_T values ranged from 1.28 mL/cm³ cerebellum 3.71 putamen, <i>BP</i>_ND 0.25 temporal cortex 1.92 putamen. estimated simplified reference tissue (SRTM) similar those MA1. Test–retest variability high-binding (striatum) 4% ± 6% MA1 <i>V</i>_T, 13% <i>BP</i>_ND, 7% SRTM respectively. Pretreatment animals inhibitor PF-05180999 resulted dose-dependent reduction binding, half maximal effective 69.4 ng/mL plasma concentration. <b>Conclusion:</b>¹⁸F-PF-05270430 displayed fast reversible kinetics primates, as blockable inhibitor. This first tracer desirable properties demonstrated ability image quantify vivo.