Development of Tc-99m labeled long chain fatty acid derivative for myocardial imaging

C-11和I-123标记的长链脂肪酸衍生物已被报道为评估心肌脂肪酸代谢的有用放射性药物。我们已经报道了中链脂肪酸衍生物~(99)m和~(99)m-Tc-MAMA-HA在肝脏中通过β-氧化代谢，而MAMA配体与~(99m)Tc作为螯合基团连接在脂肪酸衍生物的欧米位上。基于这些发现，我们致力于开发反映心肌脂肪酸代谢的标记长链脂肪酸衍生物，合成了一些分子中含有MAMA基团的长链脂肪酸(碳长：11(MAMA-DA)，15(MAMA-HDA))，作为与TC-99m的螯合基团。合成完成后，在稀乙醇溶液中，通过配体交换反应，将99m-高铁酸盐与葡萄糖庚糖酸亚锡还原后进行标记，并用高效液相系统进行纯化。以~gt；70%的放化产率和~gt；95%的放化纯度获得了~(99)m标记的长链脂肪酸衍生物。在小鼠体内动物实验中观察到较高的初始摄取。此值是I-125-IPPA(对碘苯基十五烷酸)的一半。以原代培养的成年大鼠心肌细胞为研究对象，研究了~(99m)Tc-MAMA-HDA的β氧化反应。对代谢产物进行放射薄层色谱分析。提示~(99m)Tm-MAMA-HDA在体外可被心肌代谢成短链脂肪酸衍生物，初步认为~(99)m-MAMA-HDA可能是心肌中的一种长链脂肪酸。这种~(99m)Tc标记化合物可用于评价心肌中的脂肪酸代谢。

C-11 and I-123 labeled long chain fatty acid derivatives have been reported as useful radiopharmaceuticals for estimation of myocardial fatty acid metabolism. We have reported that ^<99m>Tc-MAMA-HA, middle chain fatty acid derivative, is metabolized by beta-oxidation in a liver and MAMA ligand is useful to attach to the omega-position of fatty acid derivative as a chelating group with Tc-99m. Based on these findings, we focused on developing Tc-99m labeled long chain fatty acid derivative that reflected fatty acid metabolism in the myocardium.We synthesized some long chain fatty acids (carbon length ; 11 (MAMA-DA), 15 (MAMA-HDA)) containing MAMA group in its molecule as a chelating group with Tc-99m. After the synthesis, Tc-99m labeling was performed by ligand-exchange reaction with Tc-99m-pertechnetate reduced by Sn(II) glucoheptonate in diluted ethanol solution and purified with HPLC system. Tc-99m labeled long chain fatty acid derivatives were obtained with radiochemical yield of >70 % and radiochemical purity of >95 %.A Higher initial uptake of Tc-99m-MAMA-HDA was observed in in vivo animal experiments using mice. The value was half of that by I-125-IPPA (p-iodo-phenyl pentadecanoic acid). Beta oxidation of Tc-99m-MAMA-HDA was investigated using primary cell culture of adult rats myocardium as a preliminary study. The metabolites were analyzed by radio TLC. It was indicated that Tc-99m-MAMA-HDA was metabolized to a short chain fatty acid derivative by the myocardium in vitro.In conclusion, Tc-99m-MAMA-HDA may be recognized as a long chain fatty acid in the myocardium although further examination are required. This Tc-99m labeled compound is useful to evaluate fatty acid metabolism in the myocardium.