RT Journal Article
SR Electronic
T1 Targeting Somatostatin Receptors: Preclinical Evaluation of Novel <sup>18</sup>F-Fluoroethyltriazole-Tyr<sup>3</sup>-Octreotate Analogs for PET
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1441
OP 1448
DO 10.2967/jnumed.111.088906
VO 52
IS 9
A1 Julius Leyton
A1 Lisa Iddon
A1 Meg Perumal
A1 Bard Indrevoll
A1 Matthias Glaser
A1 Edward Robins
A1 Andrew J.T. George
A1 Alan Cuthbertson
A1 Sajinder K. Luthra
A1 Eric O. Aboagye
YR 2011
UL http://jnm.snmjournals.org/content/52/9/1441.abstract
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.