Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
Department of Radiology and Nuclear Medicine, Akita Cerebrospinal and Cardiovascular Center, 6-10 Senshu-Kubota Machi, Akita, 010-0874, Japan.
Ann Nucl Med. 2019 Nov;33(11):855-865. doi: 10.1007/s12149-019-01398-x. Epub 2019 Aug 30.
Two fluorine-18-labeled analogues, 3-deoxy-3-[F]fluoro-D-allose (3-[F]FDA) and 6-deoxy-6-[F]fluoro-D-allose (6-[F]FDA), were synthesized and their potentials of diagnostic property were characterized.
In vitro rat red blood cell (RBC) transport and phosphorylation by yeast hexokinase were evaluated in comparison with 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG). The rate of protein binding in pooled human serum was measured by an ultrafiltration method. In vivo metabolite analysis in mice was also performed. Biodistribution, urine excretion, and in vivo renal kinetics in mice were compared with 2-deoxy-2-[F]fluorosorbitol ([F]FDS).
Rat RBC uptake of 3- and 6-[F]FDA (7.8 ± 2.5%ID and 10.2 ± 4.8%ID, respectively) was significantly lower than that of [F]FDG (44.7 ± 8.7%ID). RBC uptake of 3-[F]FDA was inhibited by D-glucose (30%) and cytochalasin B (40%), indicating the involvement of GLUT1-dependent transport. In contrast, 6-[F]FDA transport was not inhibited by D-glucose and cytochalasin B. 3- and 6-[F]FDA were not phosphorylated by yeast hexokinase under the conditions that result in 60% conversion of [F]FDG into [F]FDG-6-phosphate within 30 min. Serum protein binding of 3- and 6-[F]FDA was negligible. Metabolic transformation of both tracers was not detected in plasma and urine at 30 min after injection. The highest tissue uptake of both tracers was observed in kidneys. Heart and brain uptake of both tracers was below blood levels throughout the biodistribution studies (until 120 min after injection). No significant uptake in the bone was observed, indicating the absence of de-fluorination in mice. In vivo PET imaging visualized rapid excretion of the administered 3- and 6-[F]FDA from the kidneys, with minimal tracer accumulation in other organs. The urine excretion rate of 3-[F]FDA was much lower than that of 6-[F]FDA and [F]FDS.
3- and 6-[F]FDA might be unsatisfactory for tumor imaging. In contrast, these tracers demonstrated high levels of kidney uptake and excretion, low serum protein binding, and high metabolic stability as preferable properties for renal imaging. Notably, the urine excretion rate and kidney uptake kinetics of 6-[F]FDA were comparable with those of the potential renal imaging agent [F]FDS. Further validation studies in animal models are required to confirm the feasibility of 6-[F]FDA as a functional renal imaging agent.
合成两种氟-18 标记的类似物，3-去氧-3-[F]氟-D-阿洛糖（3-[F]FDA）和 6-去氧-6-[F]氟-D-阿洛糖（6-[F]FDA），并对其诊断特性进行了表征。
通过与 2-脱氧-2-[F]氟-D-葡萄糖（[F]FDG）进行比较，评估了大鼠红细胞（RBC）在体外的转运和酵母己糖激酶的磷酸化作用。采用超滤法测定人血清中蛋白质的结合率。还在小鼠体内进行了代谢产物分析。比较了 3-[F]FDA 和 6-[F]FDA 在小鼠体内的生物分布、尿液排泄和体内肾脏动力学与 2-脱氧-2-[F]氟山梨醇（[F]FDS）的差异。
3-和 6-[F]FDA 的 RBC 摄取（分别为 7.8±2.5%ID 和 10.2±4.8%ID）明显低于[F]FDG（44.7±8.7%ID）。RBC 摄取 3-[F]FDA 被 D-葡萄糖（30%）和细胞松弛素 B（40%）抑制，表明涉及 GLUT1 依赖性转运。相比之下，6-[F]FDA 转运不受 D-葡萄糖和细胞松弛素 B 的抑制。在 30 分钟内将[F]FDG 转化为[F]FDG-6-磷酸的条件下，酵母己糖激酶不能磷酸化 3-和 6-[F]FDA。3-和 6-[F]FDA 与血清蛋白的结合可忽略不计。在注射后 30 分钟，在血浆和尿液中均未检测到两种示踪剂的代谢转化。两种示踪剂在肾脏中的组织摄取最高。在整个生物分布研究过程中（直至注射后 120 分钟），心脏和大脑中的示踪剂摄取均低于血液水平。骨骼中未观察到明显摄取，表明在小鼠中不存在脱氟作用。体内 PET 成像显示，3-和 6-[F]FDA 从肾脏迅速排泄，其他器官中示踪剂的蓄积很少。3-[F]FDA 的尿液排泄率远低于 6-[F]FDA 和[F]FDS。
3-和 6-[F]FDA 可能不适合肿瘤成像。相比之下，这些示踪剂表现出高肾脏摄取和排泄水平、低血清蛋白结合率和高代谢稳定性，是肾脏成像的理想特性。值得注意的是，6-[F]FDA 的尿液排泄率和肾脏摄取动力学与潜在的肾脏成像剂[F]FDS 相当。需要在动物模型中进行进一步的验证研究，以确认 6-[F]FDA 作为功能性肾脏成像剂的可行性。
