Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET

Journal of Nuclear Medicine

Lisa Iddon¹  Julius Leyton¹  Meg Perumal¹  Edward Robins¹  Alan Cuthbertson¹  Bard Indrevoll¹  Eric O. Aboagye¹  Andrew J.T. George¹  Matthias Glaser¹  Sajinder K. Luthra¹ 

关键词: somatostatin receptor;    octreotide;    ¹⁸F-fluoroethyl-triazole-Tyr³-octreotate;    positron emission tomography;    and neuroendocrine;   

DOI  :  10.2967/jnumed.111.088906

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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-2on the cell surface of these tumors, 111In-diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. 18F-radiolabeled analogs with suitable pharmacokinetics would permit PET with more rapid clinical protocols. Methods: We compared the affinity in vitro and tissue pharmacokinetics by PET of 5 structurally related 19F/18F-fluoroethyltriazole-Tyr3-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 18F-aluminum fluoride NOTA-octreotide (18F-AIF-NOTA-OC) and the clinical radiotracer 68Ga-DOTATATE. Results: All 19F-fluoroethyltriazole-Tyr3-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 18F-FET-G-PEG-TOCA and 18F-FETE-PEG-TOCA, reduced uptake in high sstr-2–expressing AR42J pancreatic cancer xenografts. 18F-FET-βAG-TOCA showed the lowest nonspecific uptake in the liver. Tumor uptake increased in the order 68Ga-DOTATATE < 18F-AIF-NOTA ≤ 18F-FET-βAG-TOCA < 18F-FET-G-TOCA. The uptake of 18F-FET-βAG-TOCA was specific: a radiolabeled scrambled peptide, 18F-FET-βAG-[W-c-(CTFTYC)K], did not show tumor uptake; there was lower uptake of 18F-FET-βAG-TOCA in AR42J xenografts when mice were pretreated with 10 mg of unlabeled octreotide per kilogram; and there was low uptake of 18F-FET-βAG-TOCA in low sstr-2–expressing HCT116 xenografts. Conclusion: We have developed novel fluoroethyltriazole-Tyr3-octreotate radioligands that combine high specific binding with rapid target localization and rapid pharmacokinetics for high-contrast PET. 18F-FET-βAG-TOCA and 18F-FET-G-TOCA are candidates for future clinical evaluation.

【 授权许可】

Unknown