School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, United Kingdom.
School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, United Kingdom.
Nucl Med Biol. 2020 Sep-Oct;88-89:24-33. doi: 10.1016/j.nucmedbio.2020.07.002. Epub 2020 Jul 6.
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 ([C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging.
[C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([C]CO) and 3-pyridineboronic acid ester via a copper-mediated reaction. [C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [C]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) [C]niacin formulations were administered orally.
Total synthesis time including HPLC purification was 25 ± 1 min from end of [C]CO delivery. [C]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 [C]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 [C]niacin. Pre-administration of AZD3965 selectively decreased [C]niacin uptake in MCT1-expressing organs such as heart and retina. Following oral administration of NCA [C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the excretory organs.
Here, we describe the efficient preparation of [C]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.
足够的烟酸摄入对细胞的正常功能至关重要。烟酸通过单羧酸转运蛋白进入细胞：钠离子依赖的单羧酸转运蛋白（SMCT1 和 SMCT2）和单羧酸转运蛋白（MCT1）。尽管烟酸在生物系统中很重要，但令人惊讶的是，它在活生物体中的体内分布和运输尚未得到报道。用短寿命正电子发射放射性核素碳-11（[C]烟酸）标记烟酸，将使使用体内 PET 分子成像对这种内源性微量营养素运输进行定量体内研究成为可能。
[C]烟酸通过在全自动系统中使用回旋加速器产生的二氧化碳（[C]CO）和 3-吡啶硼酸酯进行简单的一步一步一锅反应合成，通过铜介导的反应。[C]烟酸在放置在高分辨率 nanoScan PET/CT 扫描仪中的健康麻醉小鼠中静脉内给药。为了进一步表征体内[C]烟酸的分布，用烟酸或 AZD3965 （一种有效的、选择性的 MCT1 抑制剂）对小鼠进行处理。为了研究体内烟酸的胃肠道吸收和分布，给予无载体添加（NCA）和载体添加（CA）[C]烟酸制剂口服。
从[C]CO 输送结束到总合成时间（包括 HPLC 纯化）为 25±1 分钟。[C]烟酸的放射性化学产率为 17±2%，经衰变校正。我们报告了静脉内给予[C]烟酸后肾脏、心脏、眼睛和肝脏中放射性迅速积累，这与已知的体内 SMCTs 和 MCT1 转运体组织表达一致。预先给予非放射性烟酸可减少肾脏、心脏、眼部和肝脏摄取，并增加[C]烟酸的尿排泄。预先给予 AZD3965 可选择性地减少心脏和视网膜等 MCT1 表达器官中[C]烟酸的摄取。口服 NCA [C]烟酸后，大量放射性物质积聚在肠道中。CA 消除了[C]烟酸在肠道中的积聚，导致其优先分布到表达烟酸转运体的所有组织和排泄器官。
在这里，我们描述了[C]烟酸作为 PET 成像剂的有效制备方法，用于通过静脉内和口服给药来探测健康啮齿动物中营养需求的运输，提供了一种可转化的技术，使未来能够探索人类烟酸的运输，并评估其作为代谢紊乱（血脂异常）和癌症研究工具的应用。
