Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain
Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain
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DOI：
10.1002/jlcr.3056
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发表时间：
2013-09-01
影响因子：
1.8
通讯作者：
Tsukada, Hideo
中科院分区：
文献类型：
--
作者：
Harada, Norihiro;Nishiyama, Shingo;Tsukada, Hideo
我们开发了三个小说正电子发射断层扫描(PET)探针,2-tert-butyl-4-chloro-5 - {6 - [2 - (2 [f - 18] fluoroethoxy)乙氧基的]-pyridin-3-ylmethoxy} 2 h-pyridazin-3-one ([f - 18] BCPP-EF) 2-tert-butyl-4-chloro-5 - [6 - (4 - (f - 18) fluorobutoxy) -pyridin-3-ylmethoxy] 2 h-pyridazin-3-one ([f - 18] BCPP-BF)和2-tert-butyl-4-chloro-5——{6 - [2 - (2 - (C-11) methoxy-ethoxy)乙氧基的]-pyridin-3-ylmethoxy} 2 h-pyridazin-3-one ([C-11] BCPP-EM),定量成像的线粒体体内复杂的1 (MC-1)活动。这三种PET探针通过亲核的[F-18]氟化或相应前体的[C-11]甲基化成功标记，具有足够的放射性产率、良好的放射化学纯度和足够高的PET测量比放射性。用鱼藤酮（一种特异性MC-1抑制剂）体外大鼠脑切片成像方法评估这些探针与MC-1结合的特异性。通过小动物PET进行的大鼠全身成像显示，所有探针在大脑和心脏中都显示出高水平的摄取，足以清晰地成像。注射后刚脑和心脏的摄取水平排序为：[F-18]BCPP-BF高，[C-11]BCPP-EM中等，[F-18]BCPP-EF低。[F-18]BCPP-EF和[C-11]BCPP-EM的动力学表现为可逆结合模式，而[F-18]BCPP-BF在脑和心脏中表现为不可逆蓄积型动力学。代谢物分析表明，这三种化合物在血浆中代谢迅速，但在注射后60min内在大鼠脑中相对稳定。本研究表明[F-18]BCPP-EF可以作为PET定量成像活脑MC-1活性的有效PET探针。
We developed three novel positron-emission tomography (PET) probes, 2-tert-butyl-4-chloro-5-{6-[2-(2[F-18]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([F-18]BCPP-EF), 2-tert-butyl-4-chloro-5-[6-(4-[F-18]fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one ([F-18]BCPP-BF), and 2-tert-butyl-4-chloro-5-{6-[2-(2-[C-11]methoxy-ethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([C-11]BCPP-EM), for quantitative imaging of mitochondrial complex 1 (MC-1) activity in vivo. These three PET probes were successfully labeled by nucleophilic [F-18]fluorination or by [C-11]methylation of their corresponding precursor with sufficient radioactivity yield, good radiochemical purity, and sufficiently high specific radioactivity for PET measurement. The specificity of these probes for binding to MC-1 was assessed with rotenone, a specific MC-1 inhibitor, by a rat brain slice imaging method in vitro. Rat whole-body imaging by small-animal PET demonstrated that all probes showed high uptake levels in the brain as well as in the heart sufficient to image them clearly. The rank order of uptake levels in the brain and the heart just after injection was as follows: high in [F-18]BCPP-BF, intermediate in [C-11]BCPP-EM, and low in [F-18]BCPP-EF. The kinetics of [F-18]BCPP-EF and [C-11]BCPP-EM provided a reversible binding pattern, whereas [F-18]BCPP-BF showed nonreversible accumulation-type kinetics in the brain and heart. Metabolite analyses indicated that these three compounds were rapidly metabolized in the plasma but relatively stable in the rat brain up to 60min post-injection. The present study demonstrated that [F-18]BCPP-EF could be a useful PET probe for quantitative imaging of MC-1 activity in the living brain by PET.