Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis
Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis
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DOI：
10.1016/j.nucmedbio.2005.03.001
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发表时间：
2005-07-01
影响因子：
3.1
通讯作者：
Mach, RH
中科院分区：
文献类型：
--
作者：
Tu, ZD;Chu, WH;Mach, RH
聚（adp -核糖）聚合酶-1 （PARP-1）是真核细胞中丰富的核酶，与DNA损伤反应有关。PARP-1检测由多种基因毒性损伤诱导的单链DNA断裂。PARP-1的过度激活被认为在组织经历细胞坏死死亡中起关键作用。因此，一种可以用PET成像PARP-1水平的放射性示踪剂可以为测量各种病理条件下的坏死提供有用的工具。phenanthridinone衍生物2-(dimethylamino)- n-（5,6-二氢-6- oxoplienanthridin2 -yl）乙酰胺（PJ34）对PARP-1具有高亲和力（IC50=20 nM），是PET放射性示踪剂开发的合适先导化合物。[C-11]PJ34是由相应的去甲基前体N-（5,6-二氢-6-氧苯蒽啶-2-基）-2-（甲氨基）乙酰胺与[C-11]碘化甲基在DMF中催化合成的。放射性标记率为60%，比活性近似于2000 mCi/mu mol（衰变校正为e.o.b）。总放射性合成时间约为50分钟。在糖尿病啮齿动物模型中进行的初步体内生物分布研究表明，[C-11]PJ34在PARP-1过度激活的组织中表现出高摄取。这些数据表明[C-11]PJ34可能是一种有用的放射性示踪剂，用于成像细胞坏死死亡的组织。(c) 2005爱思唯尔公司版权所有。
Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxoplienanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC50=20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [C-11]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [C-11]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was similar to 2000 mCi/mu mol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [C-11]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [C-11]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis. (c) 2005 Elsevier Inc. All rights reserved.