Portal de Periódicos da CAPES

Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18 F-Fluoroethyltriazole-Tyr 3 -Octreotate Analogs for PET

2011; Society of Nuclear Medicine and Molecular Imaging; Volume: 52; Issue: 9 Linguagem: Inglês

10.2967/jnumed.111.088906

1535-5667

Julius Leyton, Lisa Iddon, Meg Perumal, Bård Indrevoll, Matthias Glaser, Edward G. Robins, Andrew J.T. George, Alan Cuthbertson, Sajinder K. Luthra, Eric O. Aboagye,

Neuroblastoma Research and Treatments

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. Methods: 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. Results: 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. 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. 18 F-FET-βAG-TOCA and 18 F-FET-G-TOCA are candidates for future clinical evaluation.