In Vivo Metabolic Trapping Radiotracers for Imaging Monoamine Oxidase-A and -B Enzymatic Activity.
In Vivo Metabolic Trapping Radiotracers for Imaging Monoamine Oxidase-A and -B Enzymatic Activity.
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DOI：
10.1021/acschemneuro.5b00223
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发表时间：
2015-12-16
影响因子：
5
通讯作者：
Kilbourn MR
中科院分区：
文献类型：
--
作者：
Brooks AF;Shao X;Quesada CA;Sherman P;Scott PJ;Kilbourn MR
单胺氧化酶同工酶（MAO-A和MAO-B）是参与多种生物胺代谢的重要酶，包括神经递质5-羟色胺、多巴胺和去甲肾上腺素。最近，MAO-B浓度的变化已被提出作为与阿尔茨海默病相关的神经炎症的体内标志物。用于成像MAO酶表达或活性变化的体内放射性示踪剂的先前开发利用了不可逆的炔丙胺基自杀抑制剂或高亲和力可逆结合抑制剂。作为一种替代方法，我们研究了1-[11 C]甲基-4-芳氧基-1，2，3，6-四氢吡啶作为单胺氧化酶的代谢捕获剂。MAO介导的氧化和自发水解产生1-[11 C]甲基-2，3-二氢-4-吡啶酮，作为一种亲水性代谢物，被捕获在脑组织内。在大鼠和灵长类动物脑中使用microPET成像评价了具有苯基、联苯和7-香豆素基醚的放射性示踪剂。在大鼠脑中没有观察到任何化合物对放射性示踪剂捕获的同工酶选择性，但在猴脑中，苯基醚表现出MAO-A选择性，香豆素基醚表现出MAO-B选择性。这些化合物是进一步开发具有优化的脑药代动力学和同工酶选择性的1-[11 C]甲基-4-芳氧基-1，2，3，6-四氢吡啶的先导化合物。
The isozymes of monoamine oxidase (MAO-A and MAO-B) are important enzymes involved in the metabolism of numerous biogenic amines, including the neurotransmitters serotonin, dopamine and norepinephrine. Recently, changes in concentrations of MAO-B have been proposed as an in vivo marker of neuroinflammation associated with Alzheimer’s disease. Previous developments of in vivo radiotracers for imaging changes in MAO enzyme expression or activity have utilized the irreversible propargylamine-based suicide inhibitors, or high-affinity reversibly-binding inhibitors. As an alternative approach, we have investigated 1-[11C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines as metabolic trapping agents for the monoamine oxidases. MAO-mediated oxidation and spontaneous hydrolysis yields 1-[11C]methyl-2,3-dihydro-4-pyridinone as a hydrophilic metabolite that is trapped within brain tissues. Radiotracers with phenyl, biphenyl and 7-coumarinyl ethers were evaluated using microPET imaging in rat and primate brain. No isozyme selectivity for radiotracer trapping was observed in the rat brain for any compound, but in the monkey brain the phenyl ether demonstrated MAO-A selectivity, and the coumarinyl ether showed MAO-B selectivity. These are lead compounds for further development of 1-[11C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity.
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影响因子：
6.3
作者：
Tong, Junchao;Meyer, Jeffrey H.;Kish, Stephen J.
通讯作者：
Kish, Stephen J.
影响因子：
4.7
作者：
EFANGE, SMN;MASH, D;BILLINGS, J
通讯作者：
BILLINGS, J
影响因子：
5.3
作者：
RIACHI, NJ;HARIK, SI
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HARIK, SI
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9.3
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Carter, Stephen F.;Scholl, Michael;Nordberg, Agneta
通讯作者：
Nordberg, Agneta
影响因子：
7.3
作者：
KALGUTKAR, AS;CASTAGNOLI, K;CASTAGNOLI, N
通讯作者：
CASTAGNOLI, N