Zmuda Filip, Malviya Gaurav, Blair Adele, Boyd Marie, Chalmers Anthony J, Sutherland Andrew, Pimlott Sally L
WestCHEM, School of Chemistry, University of Glasgow , The Joseph Black Building, Glasgow G12 8QQ, U.K.
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow , Glasgow G61 1QH, U.K.
J Med Chem. 2015 Nov 12;58(21):8683-93. doi: 10.1021/acs.jmedchem.5b01324. Epub 2015 Oct 27.
Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An (123)I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [(123)I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [(123)I]5 as a noninvasive PARP-1 SPECT imaging agent.
近年来，由于聚（ADP - 核糖）聚合酶 -1（PARP -1）可作为胶质母细胞瘤的生物标志物以及PARP -1抑制剂在临床上的使用增加，人们对PARP -1的核成像兴趣日益浓厚。本研究报告了临床PARP -1抑制剂奥拉帕利的一种碘化先导类似物5作为潜在单光子发射计算机断层扫描（SPECT）成像剂的鉴定。化合物5在无细胞和细胞试验中显示为有效的PARP -1抑制剂，与奥拉帕利相比，它表现出小鼠血浆稳定性，但内在清除率大约高3倍。使用固态卤素交换方法制备了5的（123）I标记版本。在携带皮下胶质母细胞瘤异种移植瘤的小鼠中对[（123）I]5进行的体内生物分布研究表明，该示踪剂能够保留在肿瘤组织中并特异性结合PARP -1。这些发现支持对[（123）I]5作为非侵入性PARP -1 SPECT成像剂进行进一步研究。
