Carbonic anhydrase IX-targeted small molecule radiopharmaceuticals: A review of their role in clear cell renal cell carcinoma theranostics.

BACKGROUND

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer subtype, representing 70-80% of cases. Its unique molecular profile and therapeutic resistance make it a key focus in oncology. Recent advances in targeting the ccRCC-specific biomarker carbonic anhydrase IX (CAIX), especially through radiolabeled small-molecule inhibitors, are revolutionizing its management.

METHODS

We conducted a systematic literature search using PubMed, Web of Science, ACS, and CAS databases to identify promising small-molecule CAIX-targeted radiopharmaceuticals for ccRCC published between 2011 and early 2026.

RESULTS

This review systematically outlines the biology and pathological role of CAIX in ccRCC, and surveys the landscape of CAIX-targeted radioligands under investigation-from acetazolamide and benzenesulfonamide to cyclic peptide-based probes. It also presents single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging results for selected promising candidates. We critically assess the current state and promise of theranostics, highlighting future directions and challenges. By summarizing key clinical findings, this work aims to inform the development of CAIX-targeted radiopharmaceuticals and to promote precision medicine in ccRCC.

CONCLUSIONS

[68Ga]Ga-NY104, [99mTc]Tc-PHC-102, [68Ga]Ga-DPI-4452, [18F]F-VM4-037 and [18F]F-U-104 exhibit promising CAIX targeting. Structural optimization of these compounds holds promise for developing CAIX inhibitors with enhanced selectivity and lower toxicity for ccRCC therapy. At the clinical translation level, a series of novel probes represented by [68Ga]Ga-NY104 and [64Cu]Cu-PD-32766 have entered clinical investigation, enabling high-sensitivity and high-specificity detection of both primary and metastatic ccRCC lesions via PET/CT imaging. Moreover, theranostic platforms based on identical molecular scaffolds (e.g., US2 platform, DPI-4452) have laid the foundation for a "see-and-treat" precision medicine paradigm.