Click‐Chemistry (CuAAC) Trimerization of an α_vβ₆ Integrin Targeting Ga‐68‐Peptide: Enhanced Contrast for in‐Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts

Abstract

α v β 6 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 β 6 integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the α v β 6-specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH 2) to enhance α v β 6 integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP (SDM17) 3 showed a 28-fold higher α v β 6 affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC 50 of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC 50-based selectivity over the related integrin α v β 8 (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.

Tracking a TGF-β activator in vivo: sensitive PET imaging of αvβ8-integrin with the Ga-68-labeled cyclic RGD octapeptide trimer Ga-68-Triveoctin

“…Several studies have shown quite consistently that combining more than a single copy of a given targeting molecule (frequently referred to as multimerization) reliably increases the overall avidity of such constructs (for examples featuring RGD peptides, see refs [ 26 , 34 – 39 ]), and ligand multiplicity is normally correlated to target uptake [ 40 ] (we are only aware of a single counterexample reported) [ 38 ]. However, multimerization does not necessarily improve the image quality or the overall diagnostic value, most likely because the larger molecular size and a different polarity profile (as compared to the respective monomers) frequently spoils the fundamental pharmacokinetic properties, for instance, increases unspecific organ uptake and -retention, or alters the excretion route and -velocity [ 40 ].…”

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

“…Another approach builds on the concept of increased affinity and tumor retention of integrin multimers, presenting a 68 Ga-labeled trimeric conjugate of the αvβ6-specific cyclic pentapeptide SDM17 (ligand 15 , Figure 7 ) [ 359 ]. 68 Ga-TRAP(SDM17) 3 featured an affinity that increased from 7.4 to 0.26 nM, an improved selectivity for αvβ6, and a 3-fold higher tumor uptake compared to its monomer 68 Ga-TRAP(SDM17) [ 419 ]. This indicates that multimerization is also a promising strategy in αvβ6 imaging with the potential to improve imaging characteristics over monomeric compounds.…”

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics

“…Baranyai et al optimized a procedure for the conjugation of 1,4,7-triazacyclononane-1,4,7-tris(methylene(2-carboxyethylphosphinic acid)) chelator (TRAP) with peptides using CuAAC [ 108 ]. The TRAP conjugates showed kinetic inertness and suitability for 64 Cu- and 68 Ga-coordination [ 109 , 110 ].…”