Targeting somatostatin receptors: preclinical evaluation of novel 18F-fluoroethyltriazole-Tyr3-octreotate analogs for PET.

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, In-111-diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. F-18-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 F-19/F-18-fluoroethyltriazole-Tyr(3)-octreotate (FET-TOCA) analogs: FET-G-polyethylene glycol (PEG)-TOCA, FETE-PEG-TOCA, FET-G-TOCA, FETE-TOCA, and FET-beta AG-TOCA to the recently described F-18-aluminum fluoride NOTA-octreotide (F-18-AIF-NOTA-OC) and the clinical radiotracer Ga-68-DOTATATE. Results: All F-19-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 F-18-FET-G-PEG-TOCA and F-18-FETE-PEG-TOCA, reduced uptake in high sstr-2-expressing AR42J pancreatic cancer xenografts. F-18-FET-beta AG-TOCA showed the lowest nonspecific uptake in the liver. Tumor uptake increased in the order Ga-68-DOTATATE < F-18-AIF-NOTA <= F-18-FET-beta AG-TOCA < F-18-FET-G-TOCA. The uptake of F-18-FET-beta AG-TOCA was specific: a radiolabeled scrambled peptide, F-18-FET-beta AG-[W-c-(CTFTYC) K], did not show tumor uptake; there was lower uptake of F-18-FET-beta AG-TOCA in AR42J xenografts when mice were pretreated with 10 mg of unlabeled octreotide per kilogram; and there was low uptake of F-18-FET-beta AG-TOCA in low sstr-2-expressing HCT116 xenografts. Conclusion: 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. F-18-FET-beta AG-TOCA and F-18-FET- G-TOCA are candidates for future clinical evaluation.