From Metabolism to Molecular Phenotype: Carbonic Anhydrase IX–Targeted [ 68 Ga]Ga-DPI-4452 PET/CT in Renal Cell Carcinoma: A Prospective Multicenter Comparison with [ 18 F]FDG PET/CT

The objective of this study was to prospectively compare the diagnostic performance, lesion detection capability, and clinical staging impact of [68Ga]Ga-DPI-4452 PET/CT with that of [18F]FDG PET/CT in renal cell carcinoma (RCC) using a multicenter design. Methods: Sixty-eight patients with RCC were prospectively enrolled, including patients with newly diagnosed primary tumors, patients under active surveillance or ongoing systemic treatment, and patients with suspected recurrent or metastatic disease. Both PET/CT scans were performed within the same week. The primary endpoint was patient-based diagnostic accuracy; secondary endpoints included lesion detection rate, SUVmax, maximum tumor-to-background ratio, clinical management impact, and adverse events. Results: The median age was 59.5 y; 52 patients (76.5%) were men. Overall diagnostic accuracy was 92.6% for [68Ga]Ga-DPI-4452 PET/CT versus 80.9% for [18F]FDG PET/CT (P = 0.1435). In the clear cell RCC (ccRCC) subgroup (n = 56), accuracy was 98.2% versus 76.8%, respectively (P = 0.0034). [68Ga]Ga-DPI-4452 detected 90.9% of all lesions (97.9% in ccRCC), compared with 56.7% (47.1% in ccRCC) for [18F]FDG. Median SUVmax was 19.7 versus 4.3, and median of the maximum tumor-to-background ratio was 19.8 versus 2.1 for [68Ga]Ga-DPI-4452 versus [18F]FDG (both P < 0.001). In the ccRCC subgroup, [68Ga]Ga-DPI-4452 led to clinical management changes in 21 patients (37.5%), compared with 1 patient (1.8%) for [18F]FDG. No adverse events were observed. Conclusion: [68Ga]Ga-DPI-4452 PET/CT provides superior lesion detection, tumor-to-background contrast, and diagnostic accuracy compared with [18F]FDG PET/CT in ccRCC, reflecting direct visualization and targeting of the von Hippel–Lindau, hypoxia-inducible factor, and carbonic anhydrase IX axis. With its rapid pharmacokinetic profile and theranostic potential, [68Ga]Ga-DPI-4452 may represent a new molecular imaging standard in ccRCC.