The role of non-FDG agents in PET imaging of bladder cancer.

Bladder cancer (BC) poses significant diagnostic challenges for molecular imaging, as [18F]FDG PET/CT demonstrates not only intense urinary excretion that obscures pelvic lesions but also inherently limited diagnostic accuracy in differentiating tumor from inflammation and in detecting small or low-grade lesions. These shortcomings have spurred the development of non-FDG PET tracers aimed at improving lesion detectability and providing more tumor-specific information. Early-generation tracers such as [11C]acetate, [11C]/[18F]choline, [18F]fluciclovine, [11C]methionine, as well as PSMA-targeted agents demonstrated feasibility for imaging primary and recurrent disease but offered modest sensitivity for nodal or distant metastases, restricting their clinical impact. In contrast, novel molecularly targeted agents, including fibroblast activation protein (FAP) inhibitors and Nectin-4-directed ligands, have emerged as promising tracers with high tumor-to-background ratios, less urinary clearance, and strong correlation with histopathologic markers. [68Ga]FAPI PET has shown superior lesion detection and staging performance compared with [18F]FDG, while Nectin-4 PET offers potential for precision imaging and theranostic integration with antibody-drug conjugate therapies. Collectively, these advances signal a shift from conventional metabolic imaging toward receptor-targeted, biologically driven PET approaches that enable more accurate, personalized assessment of bladder cancer.