Tracking a TGF-ß activator in vivo: sensitive PET imaging of αvß8-integrin with the Ga-68-labeled cyclic RGD octapeptide trimer Ga-68-Triveoctin.

PURPOSE: As a major activator of transforming growth factor ß (TGF-ß), the RGD receptor αvß8-integrin is involved in pathogenic processes related to TGF-ß dysregulation, such as tumor growth, invasion, and radiochemoresistance, metastasis and tumor cell stemness, as well as epithelial-mesenchymal transition. The novel positron emission tomography (PET) radiopharmaceutical Ga-68-Triveoctin for in vivo mapping of αvß8-integrin expression might enhance the prognosis of certain tumor entities, as well as support and augment TGF-ß-targeted therapeutic approaches. METHODS: Monomeric and trimeric conjugates of cyclo(GLRGDLp(NMe)K(pent-4-ynoic amide)) were synthesized by click chemistry (CuAAC), labeled with Ga-68, and evaluated in MeWo (human melanoma) xenografted SCID mice by means of PET and ex-vivo biodistribution. αvß8-integrin expression in murine tissues was determined by ß8-IHC. A human subject received a single injection of 173 MBq of Ga-68-Triveoctin and underwent 3 subsequent PET/CT scans at 25, 45, and 90 min p.i.. RESULTS: The trimer Ga-68-Triveoctin exhibits a 6.7-fold higher αvß8-integrin affinity than the monomer (IC50 of 5.7 vs. 38 nM, respectively). Accordingly, biodistribution showed a higher tumor uptake (1.9 vs. 1.0%IA/g, respectively) but a similar baseline upon blockade (0.25%IA/g for both). IHC showed an intermediate ß8-expression in the tumor while most organs and tissues were found ß8-negative. Low non-target tissue uptakes (< 0.4%IA/g) confirmed a low degree of unspecific binding. Due to its hydrophilicity (log D = - 3.1), Ga-68-Triveoctin is excreted renally and shows favorable tumor/tissue ratios in mice (t/blood: 6.7; t/liver: 6.8; t/muscle: 29). A high kidney uptake in mice (kidney-to-blood and -to-muscle ratios of 126 and 505, respectively) is not reflected by human PET (corresponding values are 15 and 30, respectively), which furthermore showed notable uptakes in coeliac and choroid plexus (SUVmean 6.1 and 9.7, respectively, 90 min p.i.). CONCLUSION: Ga-68-Triveoctin enables sensitive in-vivo imaging αvß8-integrin expression in murine tumor xenografts. PET in a human subject confirmed a favorable biodistribution, underscoring the potential of Ga-68-Triveoctin for mapping of αvß8-integrin expression in a clinical setting.