[68Ga]Ga-14

Clear-cell renal cell carcinoma (ccRCC) represents the predominant histological subtype of renal carcinoma and accounts for the majority of kidney cancer-related deaths. Conventional [¹⁸F]FDG PET frequently fails to detect ccRCC because of its intrinsically low glucose metabolism. Carbonic anhydrase IX (CAIX), a hypoxia-inducible, tumor-specific cell-surface enzyme that is highly expressed in nearly all ccRCCs but absent from healthy kidney tissue, represents an attractive alternative target. Here, we developed a panel of modularly designed ⁶⁸Ga-labeled acetazolamide analogues incorporating varied linkers and chelators. Among these, [⁶⁸Ga]Ga-14 demonstrated the most favorable overall profile, including high stability and optimized pharmacokinetics. [⁶⁸Ga]Ga-14 bound recombinant human CAIX with high affinity (IC₅₀ = 61 ± 9.5 nM). In OS-RC-2 xenograft models, it achieved superior tumor uptake (SUV_max = 1.41 ± 0.04) and tumor-to-muscle ratio (9.68) at 1 h post-injection. Despite gradual tumor washout, rapid clearance from non-target tissues increased the tumor-to-muscle ratio to 14.92 at 2 h. CAIX specificity was validated by a blocking study in which excess inhibitor reduced tumor uptake by 95 %. These findings identify [⁶⁸Ga]Ga-14 as a highly promising CAIX-targeted PET tracer for sensitive detection of ccRCC, with potential for future theranostic applications.