Imaging niacin trafficking with positron emission tomography reveals in vivo monocarboxylate transporter distribution.
Imaging niacin trafficking with positron emission tomography reveals in vivo monocarboxylate transporter distribution.
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DOI：
10.1016/j.nucmedbio.2020.07.002
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发表时间：
2020-09
影响因子：
3.1
通讯作者：
Gee A
中科院分区：
文献类型：
--
作者：
Bongarzone S;Barbon E;Ferocino A;Alsulaimani L;Dunn J;Kim J;Sunassee K;Gee A
充足的维生素烟酸的饮食摄入对于正常的细胞功能是必不可少的。烟酸通过单羧酸转运蛋白：钠依赖性单羧酸转运蛋白（SMCT 1和SMCT 2）和单羧酸转运蛋白（MCT 1）转运到细胞中。尽管烟酸在生物系统中的重要性，但令人惊讶的是，其在活生物体中的体内生物分布和运输尚未报道。烟酸放射性标记的短寿命的正电子发射放射性核素碳-11（[11 C]烟酸）的可用性将使定量体内研究这种内源性微量营养素运输使用体内PET分子成像。[11 C]烟酸是通过一个简单的一步，一锅反应，在一个完全自动化的系统中使用回旋加速器产生的二氧化碳（[11 C]CO2）和3-吡啶硼酸酯通过铜介导的反应合成的。[11 C]烟酸静脉注射到置于高分辨率nanoScan PET/CT扫描仪中的健康麻醉小鼠中。为了进一步表征体内[11 C]烟酸的体内分布，用烟酸或AZD 3965（一种强效和选择性MCT 1抑制剂）激发小鼠。为了检查烟酸的胃肠道吸收和体内分布，口服给予无载体添加（NCA）和载体添加（CA）[11 C]烟酸制剂。从[11 C]CO2输送结束算起，包括HPLC纯化在内的总合成时间为25 ± 1 min。[11 C]烟酸的衰变校正放射化学产率为17 ± 2%。我们报告了静脉给药[11 C]烟酸在肾脏、心脏、眼睛和肝脏中的快速放射性蓄积，这与已知的体内SMCT和MCT 1转运蛋白组织表达一致。预先给予非放射性烟酸可降低肾脏、心脏、眼部和肝脏的摄取，并增加[11 C]烟酸的尿排泄。预先给予AZD 3965可选择性降低MCT 1表达器官（如心脏和视网膜）中的[11 C]烟酸摄取。经口给予NCA [11 C]烟酸后，肠道中蓄积了高水平的放射性。CA消除了[11 C]尼克酸的肠道积聚，导致优先分布到表达尼克酸转运蛋白的所有组织和排泄器官。在这里，我们描述了[11 C]烟酸作为PET显像剂的有效制备，用于通过静脉内和口服给药探测健康啮齿动物的营养需求的运输，提供了一种可翻译的技术，使未来的探索烟酸在人类中的运输，并评估其作为代谢紊乱（血脂异常）和癌症的研究工具的应用。
A sufficient dietary intake of the vitamin niacin is essential for normal cellular function. Niacin is transported into the cells by the monocarboxylate transporters: sodium-dependent monocarboxylate transporter (SMCT1 and SMCT2) and monocarboxylate transporter (MCT1). Despite the importance of niacin in biological systems, surprisingly, its in vivo biodistribution and trafficking in living organisms has not been reported. The availability of niacin radiolabelled with the short-lived positron emitting radionuclide carbon-11 ([11C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging. [11C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([11C]CO2) and 3-pyridineboronic acid ester via a copper-mediated reaction. [11C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [11C]niacin distribution in vivo, mice were challenged with either niacin or AZD3965, a potent and selective MCT1 inhibitor. To examine niacin gastrointestinal absorption and body distribution in vivo, no-carrier-added (NCA) and carrier-added (CA) [11C]niacin formulations were administered orally. Total synthesis time including HPLC purification was 25 ± 1 min from end of [11C]CO2 delivery. [11C]Niacin was obtained with a decay corrected radiochemical yield of 17 ± 2%. We report a rapid radioactivity accumulation in the kidney, heart, eyes and liver of intravenously administered [11C]niacin which is consistent with the known in vivo SMCTs and MCT1 transporter tissue expression. Pre-administration of non-radioactive niacin decreased kidney-, heart-, ocular- and liver-uptake and increased urinary excretion of [11C]niacin. Pre-administration of AZD3965 selectively decreased [11C]niacin uptake in MCT1-expressing organs such as heart and retina. Following oral administration of NCA [11C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [11C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the excretory organs. Here, we describe the efficient preparation of [11C]niacin as PET imaging agent for probing the trafficking of nutrient demand in healthy rodents by intravenous and oral administration, providing a translatable technique to enable the future exploration of niacin trafficking in humans and to assess its application as a research tool for metabolic disorders (dyslipidaemia) and cancer.
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影响因子：
5.5
作者：
Chidlow, G;Wood, JPM;Osborne, NN
通讯作者：
Osborne, NN
影响因子：
--
作者：
Curtis NJ;Mooney L;Hopcroft L;Michopoulos F;Whalley N;Zhong H;Murray C;Logie A;Revill M;Byth KF;Benjamin AD;Firth MA;Green S;Smith PD;Critchlow SE
通讯作者：
Critchlow SE
影响因子：
16.6
作者：
Riss, Patrick J.;Lu, Shuiyu;Telu, Sanjay;Aigbirhio, Franklin I.;Pike, Victor W.
通讯作者：
Pike, Victor W.
影响因子：
1.2
作者：
Iwanaga, Toshihiko;Takebe, Kumiko;Kuwahara, Atsukazu
通讯作者：
Kuwahara, Atsukazu
影响因子：
3.4
作者：
Fishbein, WN;Merezhinskaya, N;Foellmer, JW
通讯作者：
Foellmer, JW