Background: [⁶⁸Ga]Ga-FAPI-46 is a novel positron emission tomography (PET) ligand that targets fibroblast activation protein (FAP) expression as FAP inhibitor (FAPI) and could already show promising results in several tumor entities. It could be demonstrated that an increased FAP expression correlates with tumor aggressivity in urothelial carcinoma (UC). Given the limited value of [¹⁸F]FDG in UC, [⁶⁸Ga]Ga-FAPI-46 could add diagnostic information in staging and response assessment in UC. We present the first data of [⁶⁸Ga]Ga-FAPI-46 PET imaging in a pilot cohort of UC patients evaluating uptake characteristics in metastases and primary tumors. Methods: Fifteen patients with UC prior to or after local treatment underwent [⁶⁸Ga]Ga-FAPI-46 PET/CT imaging for detection of metastatic spread. We compared the biodistribution in non-affected organs and tumor uptake of UC lesions by standard uptake value measurements (SUV_mean and SUV_max). Additionally, metastatic sites on PET were compared to its morphological correlate on contrast-enhanced computed tomography (CT). Results: Overall, 64 tumor sites were detected on PET and/or CT. The highest uptake intensity was noted at the primary site (SUV_max 20.8 (range, 8.1–27.8)) followed by lymph node metastases (SUV_max 10.6 (range, 4.7–29.1)). In 4/15 (26.7%) patients there were [⁶⁸Ga]Ga-FAPI-46-positive lesions that were missed on standard routine CT imaging. On the other hand, 2/15 patients had suspicious prominent bipulmonary nodules as well as pelvic lymph nodes previously rated as suspicious for metastatic spread on CT, but without increased FAPI expression; here histopathology excluded malignancy. Conclusion: [⁶⁸Ga]Ga-FAPI-46 PET shows distinctly elevated uptake in UC lesions. Therefore, the tracer has potential as a promising new biomarker in metastatic UC patients, as [⁶⁸Ga]Ga-FAPI-46 PET might improve detection of metastatic sites compared to CT alone. These findings highly emphasize larger studies investigating FAPI imaging in UC patients.

Background: PSMA-based alpha therapy using ²²⁵Ac-PSMA-I&T provides treatment for metastatic castration-resistant prostate cancer (mCRPC), even after the failure of ¹⁷⁷Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcomes and plays an increasing role in mCRPC patients. Hence, we aimed to assess TTV and its changes during ²²⁵Ac-PSMA-I&T RLT. Methods: mCRPC patients undergoing RLT with ²²⁵Ac-PSMA-I&T with available ¹⁸F-PSMA-1007 PET/CT prior to therapy initiation were included. TTV was assessed in all patients using established cut-off values. Image derived, clinical and biochemistry parameters (PSA, LDH, AP, pain score) were analyzed prior to and after two cycles of ²²⁵Ac-PSMA. Changes in TTV and further parameters were directly compared and then correlated with established response criteria, such as RECIST 1.1 or mPERCIST. Results: 13 mCRPC patients were included. The median overall survival (OS) was 10 months. Prior to ²²⁵Ac-PSMA RLT, there was no significant correlation between TTV with other clinical parameters (p > 0.05 each). Between short-term survivors (STS, 0.05 each). In two patients, new PET-avid lesions were detected on ¹⁸F-PSMA-1007 PET/CT. However, TTV and PSA were decreasing or stable. Conclusion: PET-derived assessment of TTV is an easily applicable imaging biomarker independent of other established parameters prior to ²²⁵Ac-PSMA RLT in these preliminary follow-up data. Even after the failure of ¹⁷⁷Lu-PSMA, patients with extensive TTV seem to profit from RLT. All but one patient who was eligible for ≥2 cycles of ²²⁵Ac-PSMA-RLT demonstrated drastic TTV decreases without direct correlation to other biomarkers, such as serum PSA changes. Changes in TTV might hence improve the response assessment compared to standard classifiers by reflecting the current tumor load independent of the occurrence of new lesions.

In renal cell carcinoma (RCC), accurate imaging methods are required for treatment planning and response assessment to therapy. In addition, there is an urgent need for new therapeutic options, especially in metastatic RCC. One way to combine diagnostics and therapy in a so-called theranostic approach is the use of radioligands directed against surface antigens. For instance, radioligands against prostate-specific membrane antigen (PSMA) have already been successfully used for diagnosis and radionuclide therapy of metastatic prostate cancer. Recent studies have demonstrated that PSMA is expressed not only in prostate cancer but also in the neovasculature of several solid tumors, which has raised hopes to use PSMA-guided theranostic approaches in other tumor entities, too. However, data on PSMA expression in different histopathological subtypes of RCC are sparse. Because a better understanding of PSMA expression in RCC is critical to assess which patients would benefit most from theranostic approaches using PSMA-targeted ligands, we investigated the expression pattern of PSMA in different subtypes of RCC on protein level. Immunohistochemical staining for PSMA was performed on formalin-fixed, paraffin-embedded archival material of major different histological subtypes of RCC (clear cell RCC (ccRCC)), papillary RCC (pRCC) and chromophobe RCC (cpRCC). The extent and intensity of PSMA staining were scored semi-quantitatively and correlated with the histological RCC subtypes. Group comparisons were calculated with the Kruskal–Wallis test. In all cases, immunoreactivity was detected only in the tumor-associated vessels and not in tumor cells. Staining intensity was the strongest in ccRCC, followed by cpRCC and pRCC. ccRCC showed the most diffuse staining pattern, followed by cpRCC and pRCC. Our results provide a rationale for PSMA-targeted theranostic approaches in ccRCC and cpRCC.

Introduction: [⁶⁸ Ga]Ga-FAPI-46 PET/CT is a novel hybrid imaging method that previously showed additional diagnostic value in the assessment of distant urothelial carcinoma lesions. We hypothesized that patients with bladder cancer benefit from [⁶⁸ Ga]Ga-FAPI-46 PET/CT prior to radical cystectomy for locoregional lymph node staging. Materials and methods: Eighteen patients underwent [⁶⁸ Ga]Ga-FAPI-46 PET/CT for evaluation of lymph node (LN) status in predefined LN regions. Two hundred twenty-nine intraoperatively removed LN served as histopathological reference standard. Results: Urothelial carcinoma (UC) spread was found in ten LN in seven different regions (14.3%). Hereby, [⁶⁸ Ga]Ga-FAPI-46 PET/CT was positive in four out of seven regions (57.1%) and showed significantly increased FAPI uptake compared to non-pathological regions. In the remaining three out of seven (42.9%) regions, [⁶⁸ Ga]Ga-FAPI-46 PET/CT was rated negative since no pathological increased FAPI uptake was detected or the proximity of the urinary tract prevented a differentiation from physiological uptake. CT was inconspicuous in these three regions. In total, two FAP-positive LN regions were found without histopathological counterpart. Overall, sensitivity, specificity, positive predictive value, and negative predictive value were 57.1%, 95.2%, 66.7%, and 93.0% for PET imaging. Conclusion: In summary, this innovative [⁶⁸ Ga]Ga-FAPI-46 PET/CT method showed high specificity and negative predictive value in patients with bladder UC with a future potential to optimize therapy planning.

The 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging and autoradiography in the frequently used GL261 glioblastoma mouse model and aimed to generate insights into the temporal evolution of TSPO radioligand uptake in glioblastoma in a preclinical setting. We performed a longitudinal [¹⁸F]GE-180 PET imaging study from day 4 to 14 post inoculation in the orthotopic syngeneic GL261 GBM mouse model (n = 21 GBM mice, n = 3 sham mice). Contrast-enhanced computed tomography (CT) was performed at the day of the final PET scan (±1 day). [¹⁸F]GE-180 autoradiography was performed on day 7, 11 and 14 (ex vivo: n = 13 GBM mice, n = 1 sham mouse; in vitro: n = 21 GBM mice; n = 2 sham mice). Brain sections were also used for hematoxylin and eosin (H&E) staining and TSPO immunohistochemistry. [¹⁸F]GE-180 uptake in PET was elevated at the site of inoculation in GBM mice as compared to sham mice at day 11 and later (at day 14, TBR_max +27% compared to sham mice, p = 0.001). In GBM mice, [¹⁸F]GE-180 uptake continuously increased over time, e.g., at day 11, mean TBR_max +16% compared to day 4, p = 0.011. [¹⁸F]GE-180 uptake as depicted by PET was in all mice co-localized with contrast-enhancement in CT and tissue-based findings. [¹⁸F]GE-180 ex vivo and in vitro autoradiography showed highly congruent tracer distribution (r = 0.99, n = 13, p < 0.001). In conclusion, [¹⁸F]GE-180 PET imaging facilitates non-invasive in vivo monitoring of TSPO expression in the GL261 GBM mouse model. [¹⁸F]GE-180 in vitro autoradiography is a convenient surrogate for ex vivo autoradiography, allowing for straightforward identification of suitable models and scan time-points on previously generated tissue sections.