A Biphenyl-Containing Dimeric Sulfonamide PET Tracer for High-Contrast Imaging of Carbonic Anhydrase IX in Clear Cell Renal Cell Carcinoma

Abstract Carbonic Anhydrase IX (CAIX) is an attractive biomarker for clear cell renal cell carcinoma (ccRCC), but small-molecule CAIX radiotracers are often limited by insufficient tumor retention and suboptimal tumor-to-kidney contrast. Herein, we report the rational design of biphenyl-containing bivalent sulfonamide tracers and evaluation of both 68Ga and Al18F-labeled analogues. Guided by a multivalency strategy, [68Ga]Ga-CAIX-D1 and [68Ga]Ga-CAIX-N1 were developed and compared with the monomeric reference tracer [68Ga]Ga-14. In OS-RC-2 xenografts, both dimers showed higher tumor uptake, improved tumor retention, and tumor-to-kidney ratios greater than 1. The lead scaffold was further adapted to generate [18F]AlF-CAIX-N1, which displayed high tumor uptake, excellent tumor-to-muscle contrast, CAIX-specific uptake, and lower liver uptake than its 68Ga-labeled counterpart. First-in-human positron emission tomography/computed tomography (PET/CT) imaging further supported its translational feasibility. Collectively, [18F]AlF-CAIX-N1 is a promising tracer for ccRCC imaging and highlights the value of integrating bivalency with radiolabel engineering.