PT - JOURNAL ARTICLE AU - Julius Leyton AU - Lisa Iddon AU - Meg Perumal AU - Bard Indrevoll AU - Matthias Glaser AU - Edward Robins AU - Andrew J.T. George AU - Alan Cuthbertson AU - Sajinder K. Luthra AU - Eric O. Aboagye TI - Targeting Somatostatin Receptors: Preclinical Evaluation of Novel <sup>18</sup>F-Fluoroethyltriazole-Tyr<sup>3</sup>-Octreotate Analogs for PET AID - 10.2967/jnumed.111.088906 DP - 2011 Sep 01 TA - Journal of Nuclear Medicine PG - 1441--1448 VI - 52 IP - 9 4099 - http://jnm.snmjournals.org/content/52/9/1441.short 4100 - http://jnm.snmjournals.org/content/52/9/1441.full SO - J Nucl Med2011 Sep 01; 52 AB - 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, 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 &lt; 18F-AIF-NOTA ≤ 18F-FET-βAG-TOCA &lt; 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.