Ga-68-Labeled Affibody Molecule-Based Radiopharmaceutical Targeting Platelet Derived Growth Factor Receptor Beta for...

Introduction: Platelet-derived growth factor receptor beta (PDGFRβ) is a key regulator of fibrogenesis. Non-invasive imaging of PDGFRβ expression may offer a novel approach to assess fibrotic remodeling, particularly in cardiac patients' post-intervention, where fibrosis poses clinical risk. This study presents the GMP-compliant production of a novel PDGFRβ-targeted PET radiopharmaceutical, [⁶⁸Ga]Ga-DOTA-Z09591 ([⁶⁸Ga]Ga-ATH001), and its preclinical evaluation in mouse and human myocardial tissue, along with initial clinical imaging in patients with ST-elevation myocardial infarction (STEMI). Methods: The precursor was chemically synthesized and radiolabeled with gallium-68 using a fully automated, GMP-compatible system and a pharmaceutical-grade ⁶⁸Ge/⁶⁸Ga generator. Autoradiography, H&E, Sirius Red, Masson's trichrome, and IHC staining were performed on infarcted mouse hearts and human myocardial biopsies. In vivo PET/MRI with [⁶⁸Ga]Ga-ATH001, ¹⁵O-H₂O, and gadolinium contrast was conducted in STEMI patients one week post-percutaneous coronary intervention. Results: [⁶⁸Ga]Ga-ATH001 was produced with high radiochemical yield and purity. Autoradiography demonstrated specific, receptor-mediated binding of [⁶⁸Ga]Ga-ATH001, co-localizing with PDGFRβ immunoreactivity, collagen deposition, and tissue damage. In STEMI patients, focal tracer uptake was observed in infarcted myocardium correlating with MRI-detected structural abnormalities and perfusion defects on ¹⁵O-H₂O PET. Uptake in unaffected myocardium was low and homogeneous, consistent with minimal physiological PDGFRβ expression. Conclusions: [⁶⁸Ga]Ga-ATH001 was successfully developed and validated for phase 0 clinical study. The tracer demonstrated PDGFRβ-specific binding in human fibrotic myocardium and enabled non-invasive detection of myocardial fibrogenic activity in STEMI patients. These findings support further clinical evaluation of [⁶⁸Ga]Ga-ATH001 as a targeted molecular imaging agent for early assessment of post-infarction fibrosis.