Among the earlier alternative tracers evaluated in bladder cancer are 11C-/18F-choline, 11C-/acetate, and ¹¹C-methionine, which exhibit lower urinary activity than FDG and have therefore been explored for primary tumor detection and nodal staging. However, their overall performance has been inconsistent. 11C-choline and ¹¹C-acetate are generally more promising because they show relatively low urinary excretion and can depict primary tumors and some nodal disease, but reported sensitivity is variable, and false positives from inflammation can occur. ¹⁸F-choline is usually less useful in the pelvis because urinary excretion can still obscure bladder lesions. ¹¹C-methionine has also shown possible advantages in small studies and case reports, including improved lesion contrast and enhanced detection of selected recurrences or metastatic lesions. Nonetheless, these findings remain preliminary, and none have demonstrated clear or reproducible superiority over FDG PET/CT in overall staging accuracy. Further, their broader clinical adoption has also been limited by the short half-life of ¹¹C-labeled tracers, which requires an on-site cyclotron.
A more promising and biologically compelling direction is fibroblast activation protein inhibitor (FAPi) PET imaging. FAP is highly expressed on cancer-associated fibroblasts within the tumor microenvironment and is implicated in tumor progression, invasion, and metastasis. This makes it an attractive target in bladder cancer, particularly given the stromal richness of many urothelial tumors. Immunohistochemical studies have shown strong FAP expression in a substantial proportion of bladder cancer specimens, and early clinical studies suggest that FAPi PET provides significantly higher tumor-to-background contrast than FDG. Importantly, FAPi PET has demonstrated improved detection of metastatic disease, particularly in lymph nodes, lungs, and peritoneal sites, including lesions missed by FDG or conventional CT, with potential implications for clinical management. Still, enthusiasm should be balanced with caution. As with the earlier tracers, the key question is not whether FAPi PET is biologically interesting; it clearly is, but whether it will demonstrate reproducible clinical benefit across meaningful patient populations.
Another major target of interest is Nectin-4. Nectin-4 is highly overexpressed in urothelial carcinoma and has become clinically relevant given the success of enfortumab vedotin, a Nectin-4–directed antibody-drug conjugate (ADC) in advanced urothelial cancer. Because targeted therapies depend on accurate identification of patients whose tumors express the relevant biomarker, Nectin-4 imaging holds significant promise as a companion diagnostic. Early human studies with ⁶⁸Ga-labeled Nectin-4 tracers have demonstrated favorable pharmacokinetics, high lesion detection rates, and a strong correlation between tracer uptake and tissue expression. Although Nectin-4 PET may be less sensitive than FDG for some primary tumors, it appears to offer improved specificity for nodal disease and may be particularly valuable for patient selection, treatment monitoring, and investigation of resistance mechanisms.
Similarly, TROP-2–targeted PET imaging represents another emerging theranostic opportunity. TROP-2 is the target of sacituzumab govitecan, another ADC, which has shown efficacy in advanced urothelial carcinoma. Early clinical investigation of TROP-2–directed PET tracers, including novel nanobody-based agents, suggests promising pharmacokinetics and imaging performance. These tracers may eventually provide a noninvasive, whole-body method for assessing target expression and refining patient selection for targeted therapy. The review also highlights the evolving role of immune PET imaging, particularly imaging of the PD-1/PD-L1 axis. Radiolabeled antibodies such as ⁸⁹Zr-atezolizumab, ⁸⁹Zr-durvalumab, and ⁶⁴Cu-atezolizumab have demonstrated the feasibility of whole-body PD-L1 imaging in early studies. One important observation is the substantial inter- and intra-patient heterogeneity in PD-L1 expression across primary and metastatic lesions. An implication of this is that a single-site biopsy may not adequately capture the immune landscape of advanced disease. Immune PET may therefore offer a more comprehensive assessment of expression for patient stratification, longitudinal treatment monitoring, and early identification of immune-resistant disease. At present, however, this approach remains exploratory due to limited tracer availability and technical complexity. Other molecular targets have also been evaluated, including HER2, VEGF, and PSMA. HER2-directed PET has shown specific tumor uptake in selected cases, but variable and heterogeneous HER2 expression limits broader applicability. VEGF-targeted imaging appears feasible, especially in nodal metastatic disease, while PSMA PET has generally shown weak and inconsistent expression in urothelial carcinoma, particularly in high-grade and metastatic tumors. Available data suggest that FDG PET outperforms PSMA PET in this setting.
Beyond tracer development, the field is increasingly exploring radiomics and artificial intelligence (AI) in bladder cancer imaging. CT- and MRI-based radiomics have already shown potential for predicting tumor invasion depth, staging, and treatment response, and similar interest may emerge in PET-based radiomics. By extracting quantitative features related to metabolic activity, intratumoral heterogeneity, and spatial uptake patterns, AI-driven models may eventually support more accurate prediction of stage, prognosis, and therapeutic response. Challenges include urinary tracer excretion, segmentation variability, small datasets with heterogeneous populations, and a lack of standardized radiomic workflows. As such, PET radiomics and AI should currently be viewed as promising research tools rather than ready-for-routine clinical practice.
In summary, this review highlights a rapidly advancing field in which PET imaging is moving beyond FDG and toward more tumor-specific and microenvironment-based approaches. Among the novel tracers discussed, FAPi PET and Nectin-4–targeted PET appear particularly promising because of their biological relevance. Nevertheless, the overall literature remains early-stage, and the next phase of research must include prospective comparative studies, standardized imaging protocols, and correlations with pathology, outcomes, and treatment response. Continued collaboration across urology, oncology, radiology, and nuclear medicine will be essential to define the clinical role of these new technologies and whether they can be integrated into precision care pathways for bladder cancer. The real goal is to produce imaging that is more accurate, more biologically informative, and more clinically actionable.
Written by: Esther Mena, Liza Lindenberg, Susan Heng, and Peter L. Choyke
- Molecular Imaging Branch. National Cancer Institute, NIH, Bethesda, Maryland.
- Unterrainer LM, Schmid HP, Kunte SC, Holzgreve A, Toms J, Menold P, et al. (68)Ga-FAPI and (18)F-FAPI PET/CT for detection of nodal metastases prior radical cystectomy in high-risk urothelial carcinoma patients. Eur J Nucl Med Mol Imaging. 2025;52(11):3963-74.
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