title: 64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: in silico through in vivo studies.
abstract: Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3-TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.
authors.affiliation: Department of Radiology, §Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, ¶Drug Discovery Institute, ⊥Department of Pharmacology and Chemical Biology, and ▲Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania 15219, United States.
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Cai
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Dexing
authors.initials: D
authors.lastname: Zeng
authors.forename: Kim N
authors.initials: KN
authors.lastname: Nguyen
authors.forename: Jalpa
authors.initials: J
authors.lastname: Modi
authors.forename: Lirong
authors.initials: L
authors.lastname: Wang
authors.forename: Alexander G
authors.initials: AG
authors.lastname: White
authors.forename: Buck E
authors.initials: BE
authors.lastname: Rogers
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry; D057930:Click Chemistry; D003198:Computer Simulation; D003301:Copper Radioisotopes / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000188:drug therapy; D063065:Organophosphonates / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D002614:Chelating Agents; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents; D063065:Organophosphonates; D019275:Radiopharmaceuticals; D013004:Somatostatin