Comprehensive Cancer Imaging Center at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom.
J Nucl Med. 2011 Sep;52(9):1441-8. doi: 10.2967/jnumed.111.088906. Epub 2011 Aug 18.
The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors has been increasing over the past 3 decades. Because of high densities of somatostatin receptors (sstr)--mainly sstr-2--on the cell surface of these tumors, (111)In-diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. (18)F-radiolabeled analogs with suitable pharmacokinetics would permit PET with more rapid clinical protocols.
We compared the affinity in vitro and tissue pharmacokinetics by PET of 5 structurally related (19)F/(18)F-fluoroethyltriazole-Tyr(3)-octreotate (FET-TOCA) analogs: FET-G-polyethylene glycol (PEG)-TOCA, FETE-PEG-TOCA, FET-G-TOCA, FETE-TOCA, and FET-βAG-TOCA to the recently described (18)F-aluminum fluoride NOTA-octreotide ((18)F-AIF-NOTA-OC) and the clinical radiotracer (68)Ga-DOTATATE.
All (19)F-fluoroethyltriazole-Tyr(3)-octreotate compounds retained high agonist binding affinity to sstr-2 in vitro (half-maximal effective concentration, 4-19 nM vs. somatostatin at 5.6 nM). Dynamic PET showed that incorporation of PEG linkers, exemplified by (18)F-FET-G-PEG-TOCA and (18)F-FETE-PEG-TOCA, reduced uptake in high sstr-2-expressing AR42J pancreatic cancer xenografts. (18)F-FET-βAG-TOCA showed the lowest nonspecific uptake in the liver. Tumor uptake increased in the order (68)Ga-DOTATATE < (18)F-AIF-NOTA ≤ (18)F-FET-βAG-TOCA < (18)F-FET-G-TOCA. The uptake of (18)F-FET-βAG-TOCA was specific: a radiolabeled scrambled peptide, (18)F-FET-βAG-[W-c-(CTFTYC)K], did not show tumor uptake; there was lower uptake of (18)F-FET-βAG-TOCA in AR42J xenografts when mice were pretreated with 10 mg of unlabeled octreotide per kilogram; and there was low uptake of (18)F-FET-βAG-TOCA in low sstr-2-expressing HCT116 xenografts.
We have developed novel fluoroethyltriazole-Tyr(3)-octreotate radioligands that combine high specific binding with rapid target localization and rapid pharmacokinetics for high-contrast PET. (18)F-FET-βAG-TOCA and (18)F-FET-G-TOCA are candidates for future clinical evaluation.
比较 5 种结构相关的[19]F/[18]F-氟乙基三唑-Tyr（3）-奥曲肽（FET-TOCA）类似物（FET-G-聚乙二醇（PEG）-TOCA、FETE-PEG-TOCA、FET-G-TOCA、FETE-TOCA 和 FET-βAG-TOCA）的体外亲和力和 PET 组织药代动力学，与最近描述的[18]F-铝氟化物 NOTA-奥曲肽（[18]F-AIF-NOTA-OC）和临床示踪剂[68]Ga-DOTATATE。
所有[19]F-氟乙基三唑-Tyr（3）-奥曲肽化合物在体外均保留了对 sstr-2 的高激动剂结合亲和力（半数有效浓度为 4-19 nM 与 5.6 nM 的生长抑素相比）。动态 PET 显示，含有聚乙二醇接头的化合物，如[18]F-FET-G-PEG-TOCA 和[18]F-FETE-PEG-TOCA，可降低高 sstr-2 表达的 AR42J 胰腺癌细胞异种移植中的摄取。[18]F-FET-βAG-TOCA 在肝脏中显示出最低的非特异性摄取。肿瘤摄取的顺序为[68]Ga-DOTATATE<[18]F-AIF-NOTA≤[18]F-FET-βAG-TOCA<[18]F-FET-G-TOCA。[18]F-FET-βAG-TOCA 的摄取具有特异性：放射性标记的 scrambled 肽[18]F-FET-βAG-[W-c-（CTFTYC）K] 未显示肿瘤摄取；当用 10 mg/kg 未标记的奥曲肽预处理小鼠时，AR42J 异种移植中的[18]F-FET-βAG-TOCA 摄取较低；在低 sstr-2 表达的 HCT116 异种移植中，[18]F-FET-βAG-TOCA 的摄取较低。
我们开发了新型的氟乙基三唑-Tyr（3）-奥曲肽放射性配体，它们结合了高特异性结合、快速靶向定位和快速药代动力学，可实现高对比度 PET。[18]F-FET-βAG-TOCA 和[18]F-FET-G-TOCA 是未来临床评估的候选药物。
