Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA
Philipp Backhaus, F. Gierse, Matthias C. Burg, Florian Büther, Inga Asmus, P. Dorten, J. Cufe, Wolfgang Roll, Dario Neri, Samuele Cazzamalli, Jacopo Millul, Jacqueline Mock, Andrea Galbiati, Aureliano Zana, K. P. Schäfers, Sven Hermann, Matthias Weckesser, J Tio, Stefan Wagner, Hans‐Jörg Breyholz, Michael Schäfers
Abstract
Abstract Purpose The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [ 68 Ga]Ga-OncoFAP-DOTAGA ( 68 Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. Methods 68 Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68 Ga-OncoFAP were assessed by determining log D 7.4 , IC 50 values, and radiochemical purity. 68 Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68 Ga-OncoFAP combined with PET/CT and PET/MRI. Results 68 Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68 Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting–based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68 Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUV max 12.3 ± 2.3), lymph nodes (SUV max 9.7 ± 8.3), and distant metastases (SUV max up to 20.0). Conclusion Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68 Ga-OncoFAP as a powerful alternative to currently available FAP tracers.