Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, United States.
J Med Chem. 2012 Dec 13;55(23):10674-84. doi: 10.1021/jm301345v. Epub 2012 Nov 27.
In vivo imaging of regional fatty acid oxidation (FAO) rates would have considerable potential for evaluation of mammalian diseases. We have synthesized and evaluated 18F-labeled thia fatty acid analogues as metabolically trapped FAO probes to understand the effect of chain length, degree of unsaturation, and placement of the thia substituent on myocardial uptake and retention. 18-[18F]Fluoro-4-thia-(9Z)-octadec-9-enoic acid (3) showed excellent heart/background radioactivity concentration ratios along with highest retention in heart and liver. Pretreatment of rats with the CPT-1 inhibitor, POCA, caused >80% reduction in myocardial uptake of 16-[18F]fluoro-4-thiahexadecanoic acid (2) and 3, indicating high specificity for FAO. In contrast, 18-[18F]fluoro-4-thiaoctadecanoic acid (4) showed dramatically reduced myocardial uptake and blunted response to POCA. 18-[18F]Fluoro-6-thiaoctadecanoic acid (5) showed moderate myocardial uptake and no sensitivity of myocardial uptake to POCA. The results demonstrate relationships between structures of 18F-labeled thia fatty acid and uptake and their utility as FAO probes in various tissues.
在体成像的区域脂肪酸氧化（FAO）率将有相当大的潜力评估哺乳动物疾病。我们已经合成和评估 18F 标记的噻吩脂肪酸类似物作为代谢性陷阱 FAO 探针，以了解链长，不饱和程度和噻吩取代基的位置对心肌摄取和保留的影响。18-[18F]氟-4-噻吩-（9Z）-十八-9-烯酸（3）表现出优异的心脏/背景放射性浓度比以及在心脏和肝脏中最高的保留率。用 CPT-1 抑制剂 POCA 预处理大鼠导致 16-[18F]氟-4-噻吩己酸（2）和 3 的心肌摄取减少超过 80%，表明对 FAO 具有高特异性。相比之下，18-[18F]氟-4-噻吩十八酸（4）显示出明显降低的心肌摄取和对 POCA 的反应迟钝。18-[18F]氟-6-噻吩十八酸（5）显示出适度的心肌摄取，对 POCA 的心肌摄取没有敏感性。结果表明 18F 标记的噻吩脂肪酸的结构与摄取之间存在关系，并且它们作为 FAO 探针在各种组织中的应用具有实用性。
