Synthesis and preclinical evaluation of [(11)C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain.
Synthesis and preclinical evaluation of [(11)C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain.
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DOI：
10.1007/s00259-021-05269-4
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发表时间：
2021-09
影响因子：
9.1
通讯作者：
Higuchi M
中科院分区：
文献类型：
--
作者：
Obokata N;Seki C;Hirata T;Maeda J;Ishii H;Nagai Y;Matsumura T;Takakuwa M;Fukuda H;Minamimoto T;Kawamura K;Zhang MR;Nakajima T;Saijo T;Higuchi M
磷酸二酯酶（PDE）7是神经和炎症疾病的潜在治疗靶点，尽管PDE 7的体内可视化尚未成功。在这项研究中，我们的目的是开发[11 C] MTP 38作为一种新的正电子发射断层扫描（PET）的PDE 7配体。[11 C] MTP 38是通过溴前体与[11 C]HCN的11 C-氰化反应放射合成的。用[11 C] MTP 38对大鼠和恒河猴脑进行PET扫描，并对来自这些物种的脑切片进行体外放射自显影。在猴中，使用动脉输入函数分析动态PET数据以计算总分布容积（VT）。纹状体中的不可置换结合电位（BPND）也通过具有小脑参考的参考组织模型来确定。最后，根据BPND的变化，计算猴中抑制剂对PDE 7的纹状体占有率。合成的[11 C] MTP 38放射化学纯度≥99.4%，摩尔活度为38.6 ± 12.6 GBq/μmol。放射自显影显示高放射性在纹状体和减少非放射性标记的配体，在其他地区与不变的放射自显影信号。对大鼠和猴注射放射性配体后的体内PET表明，放射性迅速分布到大脑，并在纹状体（相对于小脑）中强烈蓄积。相应地，猴纹状体和小脑中的VT估计值分别为3.59和2.69 mL/cm 3。未标记的MTP 38预处理小脑VT值不变。用PDE 7抑制剂MTP-X预处理后，纹状体BPND以剂量依赖性方式减少。MTP-X对PDE 7的结合率与血浆MTP-X浓度之间的关系可用Hill S形函数描述。我们已经提供了第一个成功的临床前演示体内PDE 7成像与特定的PET放射性配体。[11 C] MTP 38是一种可行的放射性配体，用于评估脑中的PDE 7，目前正应用于首次人体PET研究。在线版本包含补充材料，可通过10.1007/s 00259 -021-05269-4获得。
Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. [11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND. [11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function. We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study. The online version contains supplementary material available at 10.1007/s00259-021-05269-4.
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影响因子：
4.8
作者：
Kelly, Michy P.;Adamowicz, Wendy;Kleiman, Robin J.
通讯作者：
Kleiman, Robin J.
影响因子：
9.3
作者：
Naganawa, Mika;Waterhouse, Rikki N.;Carson, Richard E.
通讯作者：
Carson, Richard E.
影响因子：
3.5
作者：
Koizumi, Yuuki;Tanaka, Yoshihito;Kawanishi, Eiji
通讯作者：
Kawanishi, Eiji
影响因子：
4.2
作者：
Chen, Jie;Gu, Guibao;Tabatabaei, Ali
通讯作者：
Tabatabaei, Ali
影响因子：
6.3
作者：
LOGAN, J;FOWLER, JS;CHRISTMAN, DR
通讯作者：
CHRISTMAN, DR