title: Targeting somatostatin receptors: preclinical evaluation of novel 18F-fluoroethyltriazole-Tyr3-octreotate analogs for PET.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Comprehensive Cancer Imaging Center at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Julius
authors.initials: J
authors.lastname: Leyton
authors.forename: Lisa
authors.initials: L
authors.lastname: Iddon
authors.forename: Meg
authors.initials: M
authors.lastname: Perumal
authors.forename: Bard
authors.initials: B
authors.lastname: Indrevoll
authors.forename: Matthias
authors.initials: M
authors.lastname: Glaser
authors.forename: Edward
authors.initials: E
authors.lastname: Robins
authors.forename: Andrew J T
authors.initials: AJ
authors.lastname: George
authors.forename: Alan
authors.initials: A
authors.lastname: Cuthbertson
authors.forename: Sajinder K
authors.initials: SK
authors.lastname: Luthra
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D009942:Organometallic Compounds; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D011092:Polyethylene Glycols; C513399:gallium Ga 68 dotatate; D015282:Octreotide