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

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-?2AG-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, 4a€“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-2a€“expressing AR42J pancreatic cancer xenografts. 18F-FET-?2AG-TOCA showed the lowest nonspecific uptake in the liver. Tumor uptake increased in the order 68Ga-DOTATATE 18F-AIF-NOTA a‰¤ 18F-FET-?2AG-TOCA 18F-FET-G-TOCA. The uptake of 18F-FET-?2AG-TOCA was specific: a radiolabeled scrambled peptide, 18F-FET-?2AG-[W-c-(CTFTYC)K], did not show tumor uptake; there was lower uptake of 18F-FET-?2AG-TOCA in AR42J xenografts when mice were pretreated with 10 mg of unlabeled octreotide per kilogram; and there was low uptake of 18F-FET-?2AG-TOCA in low sstr-2a€“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-?2AG-TOCA and 18F-FET-G-TOCA are candidates for future clinical evaluation.