Click-Chemistry (CuAAC) Trimerization of an αv β6 Integrin Targeting Ga-68-Peptide: Enhanced Contrast for in-Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts

Abstract

α_v β₆ Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with α_v β₆ integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the α_v β₆ -specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH₂ ) to enhance α_v β₆ integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)₃ showed a 28-fold higher α_v β₆ affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC₅₀ of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC₅₀ -based selectivity over the related integrin α_v β₈ (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)₃ holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.

Keywords: CuAAC; integrins; positron emission tomography; radionuclides; transforming growth factor beta.