肿瘤短链脂肪酸代谢PET显像及其作用机理研究

Based on our previous development of 11C-acetate, 18F-fluoroacetate, and 2-18F-fluoropropionic acid (FPA), an assumption of "acetylCoA synthetase (ACCS) and fatty acid synthase (FASN) as potential important targets to develop short chain fatty acid metabolism PET imaging agents" is proposed by us. In this study, analogues of FPA, (R)-2-18F-fluoropropionic acid (R-FPA) and (S)-2-18F-fluoropropionic acid (S-FPA) with optical purity, and a pure compound similar to FPA, 3-18F-2,2-difluoropropionic acid (3-FPA), are attempted to be developed. 18F-β- Glutamic acid (18F-β-Glu) as a short chain fatty dicarboxylic acid imaging agent was also synthesized and evaluated. Furthermore, in vitro and in vivo biological evaluation and uptake mechanism of short chain fatty acid PET imaging agents are investigated. In order to evaluate the potential value of these PET traces and to confirm the above assumption, PET imaging of tumor-bearing nude mice is studied and compared with 18F-FDG. Through these studies, the issues related to optical synthesis of enantiomer imaging agents and rapid automated synthesis of short chain fatty acid metabolism PET imaging agents are to be solved. Therefore, this study can provide a general protocol for the development of novel positron radionuclide labeled short chain fatty acids and the investigation of its uptake mechanism. Also, the labeled short chain fatty acids tracers can be used for the early detection and therapy monitoring of malignant tumors (such as brain cancer, lung cancer, prostate cancer and liver cancer) with high specificity and sensitivity.

在先期研制11C-乙酸盐、18F-氟代乙酸盐和2-18F-氟代丙酸(FPA)基础上，提出“乙酰CoA合成酶(ACSS)和脂肪酸合成酶(FASN)是研制新型短链脂肪酸代谢PET显像剂的潜在重要靶标”的假说。本项目尝试研制具有光学活性FPA类似物R-FPA和S-FPA及其类似纯净物3-18F-2,2-二氟代丙酸(3-FPA)，并进一步研制含有两个羧基的二元短链脂肪酸代谢显像剂18F-β-Glu。研究这些目标短链脂肪酸代谢PET显像剂作用机理和体内外生物活性，用其对多种肿瘤模型动物行PET显像，以评估其用于肿瘤PET显像的潜力及证实上述假说的正确性。本项目的完成可望解决对映体显像剂光学合成问题以及现有短链脂肪酸代谢PET显像剂快速高效自动化合成难题，为肿瘤早期诊断和指导干预治疗提供短链脂肪酸代谢PET显像新方法，为新型脂肪酸代谢PET显像剂及其作用机理研究提供方法学指导。

在先期研制11C-乙酸盐、18F-氟代乙酸盐和2-18F-氟代丙酸(FPA)基础上，针对现有短链脂肪酸PET药物的缺陷，提出“脂肪酸合成酶(FASN)和三羧酸循环是研制新型短链脂肪酸PET显像剂的潜在重要靶标”的假说。本项目通过对短链单羧酸脂肪酸显像剂FPA及其对映体R-2-18F-氟代丙酸(R-FPA)和S-2-18F-氟代丙酸(S-FPA)、FPA类似物3-18F-2,2-二氟代丙酸(3-FPA)、以及二元短链脂肪酸显像剂18F标记β-谷氨酸18F-β-Glu的放射合成、质量控制、作用机理、体内外生物活性评估和PET显像的研究，发现FPA对映体R-FPA优于S-FPA，并显示与FPA相类似生物学功能和PET显像潜力；3-FPA表现出优于FPA及其对映体R-FPA和S-FPA的优良生物学功能。创制了具有优良生物学功能的二元短链脂肪酸显像剂18F-β-FPGLU和18F-AlF-NOTA-GLU。这些短链脂肪酸显像剂作用机理主要涉及FASN、三羧酸循环和/或氨基酸转运体。另外，也研制了短链单羧酸脂肪酸显像剂类似物18F标记亚氨基酸(如N-(2-18F-氟丙酰基)-L-精氨酸、N-(2-18F-氟丙酰基)-L-谷氨酰胺、N-(2-18F-氟丙酰基)-L-多巴)和18F标记侧链三氟甲基半胱氨酸显像剂，以及二元短链脂肪酸显像剂N-(2-18F-氟丙酰基)-L-谷氨酸(18F-FPGLU)和18F标记基丙二酸类似物(18F-ML-10和18F-ML-8)。此外，也研制了2-18F-氟丙酰基(18F-FP)-生物分子和复方放射性药物等。R-FPA、18F-β-FPGLU、18F-FPGLU、18F-ML-8、18F-靶向多肽和复方放射性药物是可取得自主知识产权的新型PET显像剂，具有临床转化潜力。本项目的完成为PET药物自动化合成工艺设计、创制新型单羧酸脂肪酸代谢显像剂和多价短链脂肪酸代谢显像剂的设计合成提供了方法学指导，为恶性肿瘤早期诊断和疗效监测提供靶向FASN和三羧酸循环的短链脂肪酸代谢PET显像新技术。本项目的完成也创造性地提出了复方分子探针及其显像的理论模式，为新型影像分子探针的研制提供了新思路。.本项目共发表SCI论文20篇，申请国家发明专利8项，其中授权2项，已超额完成本项目目标和任务。