RPS 906 - Hot Topic: novel radiopharmaceuticals for imaging targets and therapy

Author Block: J. Stock, A. C. Klose, F. Herr, M. J. Antons, R. Werner, J. Ricke, M. Heimer, P. M. Kazmierczak, C. C. Cyran; Munich/DE
Purpose: To evaluate whether the PET tracer [18F]-ML-10 enables early, non-invasive in vivo assessment of therapy-induced apoptotic changes in BRAF-mutant malignant melanoma under combined BRAF/MEK inhibitor treatment.
Methods or Background: A human melanoma xenograft model (A375) in 15 immunodeficient mice was used to evaluate [18F]-ML-10 PET/CT for monitoring BRAF-MEK inhibitor therapy (treatment: n = 7; control: n = 8). PET/CT scans were performed at baseline and day 7. Quantitative analysis assessed target-to-background ratios (TBR-BP, TBR-M). Histological validation included cleaved caspase-3 immunohistochemistry, TUNEL assay, and CD31 staining for microvessel density.
Results or Findings: [18F]-ML-10 PET/CT demonstrated a marked increase in [18F]-ML-10 uptake in the treatment group between baseline and follow-up but no significant change in the control group. Quantitative PET analysis revealed significantly higher TBR-BP (23.48 ± 20.61 vs. 5.81 ± 3.63; p = 0.015), and TBR-M values (42.04 ± 42.25 vs. 11.36 ± 9.54; p = 0.031) in the treatment group at follow-up. Histologically, no significant differences in apoptotic cell counts were observed between groups with cleaved caspase-3 (239.4 ± 102.7 vs. 270.4 ± 101.4 cells/HPF; p = 0.33) or TUNEL-staining (83.3 ± 34.0 vs. 64.5 ± 21.9; p = 0.29), however mean values showed a similar trend to PET results. CD31-immunohistochemistry demonstrated a significantly lower microvessel density in the treatment group (30.7 ± 10.2 vs. 43.6 ± 14.7; p = 0.041), consistent with the anti-angiogenic effects of BRAF-MEK inhibition.
Conclusion: [18F]-ML-10 PET/CT may enable non-invasive detection of therapy-associated changes suggestive of increased apoptosis in melanoma xenografts under BRAF-MEK inhibitor therapy. The findings support the potential of [18F]-ML-10 PET/CT for early therapy monitoring in targeted cancer treatment.
Limitations: Small sample size and the restriction to a single imaging time point may have limited the detection of transient apoptotic effects.
Funding for this study: Not applicable.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: All animal experiments were performed in accordance with the guidelines for the use of living animals in scientific studies and the animal study was officially approved.

Author Block: Y. Sun, Q. Sang, L. Yize, Z. Xiao; Nanjing/CN
Purpose: The therapeutic potential of chimeric antigen receptor (CAR) T-cell therapy in solid malignancies is frequently limited by inadequate infiltration, suboptimal localization, and functional exhaustion of T cells within the tumor microenvironment (TME). Previous studies have shown that targeting tumor stroma with fibroblast activation protein (FAP)-specific CAR T cells can promote T-cell penetration and suppress tumor growth in pancreatic ductal adenocarcinoma (PDAC). However, the temporal dynamics of FAP-CAR T-cell migration and their interactions with stromal and extracellular matrix (ECM) components remain poorly defined. The objective of this study was to characterize these processes to guide optimization of CAR T-cell performance in solid tumors.
Methods or Background: Multiplex immunostaining combined with intravital two-photon microscopy of PDAC tumor explants was used to assess FAP-targeted CAR T-cell behavior at defined time points. Analyses focused on localization, activation status, and migration patterns in relation to stromal and ECM structures.
Results or Findings: Within 1–3 days post-transfer, FAP-CAR T cells accumulated predominantly in stromal regions encasing tumor nests but were largely excluded from the nests themselves. In these stromal zones, CAR T cells displayed activation and migrated through areas of loosely organized collagen, whereas movement was severely hindered in dense ECM. At tumor margins, aligned collagen fibers guided T-cell migration but restricted entry into tumor nests. By day 5, depletion of immunosuppressive stromal cells and disruption of peritumoral fibrillar collagen were observed, enabling penetration of CAR T cells into tumor nests. Co-treatment with hyaluronidase further enhanced infiltration.
Conclusion: These findings indicate that stromal remodeling, achieved by depletion of FAP⁺ stromal cells and degradation of ECM, facilitates CAR T-cell accumulation and functional engagement within the desmoplastic architecture of PDAC.
Limitations: No limitations
Funding for this study: This work was supported by the National Natural Science Foundation of China （24HAA00816，82572294，32500802 and 3290002501C2 from Z.X.）
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Southeast University.

Author Block: N. Alan Selcuk, G. Beydagi, K. Akcay, A. Görmez, T. Toklu, L. Kabasakal; Istanbul/TR
Purpose: This study aimed to investigate the potential efficacy of [⁶⁸Ga]Ga-FAPi PET/CT in evaluating treatment response in patients with gastrointestinal system malignancies.
Methods or Background: Patients with gastrointestinal malignancies who underwent [⁶⁸Ga]Ga-FAPi PET/CT for treatment response assessment were included. The maximum standardized uptake values (SUVmax), total tumor volumes, and total lesion FAP expression values, tumor marker levels were recorded. Imaging responses were assessed separately according to PERCIST criteria on [⁶⁸Ga]Ga-FAPi PET/CT and RECIST criteria on CT. Survival outcomes were analyzed using Kaplan–Meier method, and their association with treatment response was assessed using Log-Rank (Mantel–Cox) test.
Results or Findings: A total of 100 [⁶⁸Ga]Ga-FAPi PET/CT scans were performed in 50 patients, both before and after treatment. Among the included patients, 70% had gastric cancer, 14% had colon cancer, 8% had pancreatic cancer, 4% had appendiceal cancer, 2% had hepatocellular carcinoma, and 2% had cholangiocellular carcinoma. A strong correlation was found between tumor volumes and total lesion FAP expression and the corresponding serum tumor markers (AUC = 0.875). There was a statistically significant and near-perfect concordance between [⁶⁸Ga]Ga-FAPi PET PERCIST and CT RECIST criteria (Kappa = 0.833, p < 0.05). Moderate agreement was found for primary tumors (Kappa = 0.526) and bone metastases (Kappa = 0.657), while excellent agreement was observed for lymph node (Kappa = 1.0), peritoneal (Kappa = 0.815), and visceral metastases (Kappa = 1.0). Treatment response assessed by [⁶⁸Ga]Ga-FAPi PET/CT was predictive of overall survival (p=0.02). Median overall survival was 7.6 months in patients with progressive disease, 19.8 months in those with stable disease and not reached in patients showing partial or complete response, as defined by PERCIST criteria.
Conclusion: [⁶⁸Ga]Ga-FAPi PET/CT appears to be an effective tool for assessing treatment response and monitoring gastrointestinal malignancies.
Limitations: N/A
Funding for this study: N/A
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Ethics Committee of Yeditepe University (Date: 02.03.2020 / No: 1576).

Author Block: Z. J. Zholdybay, M. Gabdullina, Z. Zhakenova, G. Alisherov, Z. M. Amankulov; Almaty/KZ
Purpose: We aimed to investigate the use of 68Ga-FAPI PET/CT in patients with various oncological diseases by analyzing the pathological uptake in tumors as well as physiological uptake of the tracer.
Methods or Background: Inclusion criteria included: 1) age ≥ 18 years; 2) confirmed diagnosis or clinical suspicion of a primary solid malignancy; 3) referral for cancer staging or evaluation of suspected recurrence; 4) written informed consent. Exclusion criteria included: 1) pregnancy or lactation; 2) lymphoma or melanoma; 3) known hypersensitivity or adverse reaction to the 68Ga-FAPI; 4) refusal to undergo biopsy or surgery; 5) renal impairment.
Results or Findings: Between January 10, 2024, and February 28, 2025, a total of 199 cancer patients aged 24–80 years (mean age 52.6 ± 15.4 years) were included in the study. The majority of patients (64%) were female. Indications for 68Ga-FAPI PET/CT included evaluation of primary solid tumors arising in the breast, hepatobiliary system, gastrointestinal tract, lung, head and neck region, ovary, and pancreas; a smaller subset of patients underwent imaging for less common malignancies such as choroidal tumors, histiocytic disorders, seminoma, renal neoplasms and others.
68Ga-FAPI-04 demonstrated minimal physiological uptake in normal brain regions and intestinal loops, with comparatively low activity in the liver and oropharynx. Uptake was also low in the thyroid gland, salivary glands, lung parenchyma, esophagus, myocardium, and glandular breast tissue, thereby enhancing lesion contrast in these organs.
Conclusion: In conclusion, 68Ga-FAPI-04 appears to be a promising radiotracer for the molecular imaging of most malignant neoplasms.
Limitations: First, biopsies could not be performed for all detected lesions, limiting histopathological confirmation. Second, the study was conducted in a single center. Finally, there was no direct comparison with 18F-FDG PET/CT.
Funding for this study: Committee of Science of the Ministry of Science and Higher Education of the Republic of Kazakhstan (Grant No.AP19679719)
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This prospective study was approved by the Local Ethics Committee of the Asfendiyarov Kazakh National Medical University (27 September 2023, protocol number 7 (143)).

Author Block: K. Akcay, T. Toklu, G. Beydagi, L. Kabasakal, B. Caner, N. Alan Selcuk; Istanbul/TR
Purpose: Fibroblast activation protein (FAP) is an attractive target for tumor imaging and therapy. While ⁶⁸Ga-labeled FAPi-04 and FAPi-46 are widely used diagnostically, their brief retention limits therapeutic use. FAP-2286 has emerged as a candidate for radionuclide therapy. This study evaluated the in-vitro/in-vivo stability, biodistribution, and organ/tumor dosimetry of [¹⁷⁷Lu]Lu-FAP-2286.
Methods or Background: Seven treatments were administered to five patients (mean age 61.0±15.3 years; F/M: 2/3) with positive uptake on [⁶⁸Ga]Ga-FAPi-46 or [⁶⁸Ga]Ga-FAP-2286. The mean administered activity was 215±14.7 mCi. Whole-body anterior/posterior planar scans and SPECT/CT were obtained at 4, 24, 72, and 120 h post-infusion with corrections for attenuation, scatter, and detector/collimator response. Blood samples up to 120 h supported red marrow dosimetry and in-vivo stability assessment. Whole-body ROIs and VOIs for kidneys, liver, and lesions were segmented. Time-activity curves were fitted with mono- or bi-exponentials in MATLAB R2013a to derive cumulated activities. Absorbed doses were estimated using IDAC-Dose 2.1.
Results or Findings: Two patients had pancreatic adenocarcinoma, one neuroendocrine carcinoma, and two soft-tissue sarcoma. In-vitro stability was at least 41 h; in-vivo blood stability persisted ≥24 h. Mean absorbed doses were 0.50±0.19 Gy/GBq (kidneys), 0.030±0.014 Gy/GBq (liver), and 0.054±0.014 Gy/GBq (red marrow). The mean tumor dose was 5.97±3.85 Gy (range 1.10–18.52 Gy).
Conclusion: No adverse events occurred, and all patients tolerated therapy well. At the administered activities, renal and marrow toxicity thresholds were not exceeded. Bone marrow doses were comparable to the only published series, whereas renal doses were lower. Because prior data reported doses only for bone metastases, direct comparison with the soft-tissue tumor doses presented here is not possible. Overall, [¹⁷⁷Lu]Lu-FAP-2286 shows favorable stability, dosimetry, and safety, supporting its potential as a therapeutic option across multiple malignancies.
Limitations: N/A
Funding for this study: N/A
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Ethics Committee of Yeditepe University

Author Block: H. Guo, X. Ma; Changsha, Hunan/CN
Purpose: Glypican-3 (GPC3) is upregulated in hepatocellular carcinoma (HCC), is implicated in tumor progression, and correlates with poor prognosis. These properties make it promising for both targeted immunotherapy and early detection via PET imaging. Here, we developed a novel cyclic peptide molecular probe via Phage Display Biopanning and validated the imaging ability in HCC xenografts and explored its application for HCC patients.
Methods or Background: The novel novel cyclic peptide molecular probe, namely ZSQT-3B010, was labeled with Gallium-68 (68Ga) to obtain [68Ga]Ga-ZSQT-3B010. Cell uptake assays, small-animal PET imaging, and biodistribution studies were performed to evaluate its targeting ability. Pharmacokinetics studies were confirmed in healthy volunteers (HV, n=6). In the first-in-human study, 17 patients (10 HCC and 7 Non-HCC patients) underwent [68Ga]Ga-ZSQT-3B010 PET/MR scan. Radiotracer uptake in tumors and normal tissues was quantified, and tumor-to-liver ratios (TLR) were calculated.
Results or Findings: [68Ga]Ga-ZSQT-3B010 was synthesized with high radiochemical purity and exhibited specific uptake and efficient internalization in GPC3-positive cells. [68Ga]Ga-ZSQT-3B010 effectively visualized HCC tumors, reaching a peak SUV uptake of 5.09 at 4h p.i., 3.40 and 50.00 fold higher than in GPC3 moderate and low expression tumors. The [68Ga]Ga-ZSQT-3B010 demonstrated favorable pharmacokinetics and a low radiation dose in HV. In preliminary clinical studies, no adverse events was observed. Totally 29 lesions were detected and the mean SUVmax was 15.80±3.14 at 60 min p.i. and 19.16±4.26 at 120min p.i., with a minimum detectable lesion size ≤1 cm. The TLR is 4.53-to-28.67. Further, a positive correction between GPC3 expression and SUVmax (R=0.84, P<0.05). Notably, the stomach uptake is very low compared to other reported targeted GPC3 agents.
Conclusion: The [68Ga]Ga-ZSQT-3B010 has high GPC3 binding affinity and specificity for HCC detection, and may further benifit GPC3 targeting therapy.
Limitations: No limitations were identified.
Funding for this study: Funding was provided by the Project of Research on New Targeted Peptide Radioactive Drugs for Tumor (A-202406-026-CD).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (Num：LYF20250186).

Author Block: R. Ebner, F. Herr, K. Klimek, J. Ricke, C. C. Cyran, R. Werner, G. Sheikh; Munich/DE
Purpose: Somatostatin receptor (SSR)-targeting tracer [¹⁸F]SiTATE is gaining momentum in clinical use as a promising alternative to commonly used gallium-68-labelled SSR-targeting compounds, demonstrating excellent image quality and clinical utility. Currently, imaging is performed 90 minutes after tracer injection, complicating integration into a multi-tracer PET environment, where most tracers are imaged 60 minutes after tracer injection. We therefore investigated whether comparable image quality and quantification can be achieved at earlier time points more compatible with clinical routine.
Methods or Background: Eight patients with histologically confirmed metastasized GEP-NET received [¹⁸F]SiTATE-PET/CT with repeated scans 60, 90, and 120 minutes post-injection. SUVmax, SUVpeak and SUVmean were measured in visceral organs and 49 SSR-positive lesions (lymph node, liver, bone), and tumor-to-background ratios were calculated. Statistical comparison was performed across time points. Scans were visually assessed for noticeable differences by four readers of varying experience.
Results or Findings: No significant differences in tumor-to-background ratios were observed across timepoints for liver (p=0.6613), lymph nodes (p=0.5413), bone (p=0.8478), or overall lesion assessment (p=0.7248). Post hoc multiple comparisons using tukey's test revealed no significant pairwise differences (p=0.5103–0.999). Readers did not report qualitative visual difference between the time points, all lesions could be clearly identified against the surrounding background.
Conclusion: The results demonstrate consistent tracer uptake over time, with minimal variation in tumor-to-background contrast across metastatic sites. Imaging at 60 minutes post-injection provides equivalent lesion detectability and quantitative contrast compared to 90 and 120 minutes. These findings highlight the clinical utility of early [¹⁸F]SiTATE imaging for NET patients, facilitating workflow and improving patient comfort without compromising diagnostic accuracy.
Limitations: The main limitation of our study is the small sample size and its single-center design, which may limit generalizability of the findings.
Funding for this study: None.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The data analysis received approval from the institutional ethics board of LMU Munich.

Author Block: T. Spiegel¹, D. A. Resch¹, S. Rasul¹, O. Lafcı¹, N. Pötsch¹, P. Clauser¹, P. A. Baltzer¹, K. Pinker-Domenig², T. H. Helbich¹; ¹Vienna/AT, ²New York, NY/US
Purpose: 18F-Fluoroestradiol (18F-FES) is a novel radiotracer, and little is known about its role in axillary lymph node (LN) staging in estrogen receptor (ER)-positive breast cancer (BC) on PET/MRI. This study aims to evaluate the diagnostic performance of 18F-FES-PET/MRI for axillary LN staging in ER+ BC and to define optimal thresholds.
Methods or Background: This retrospective analysis of prospectively acquired single-center study data includes 37 female patients with 38 ER+ BCs, who underwent 18F-FES-PET/MRI using a Biograph mMR system (Siemens, Germany). Semiquantitative PET parameters including SUVmax of axillary LNs were assessed by placing a volume of interest (syngo.via, Siemens) on the most suspicious LN identified on MRI. Histopathology from biopsy or surgery served as the reference standard. Statistical analysis included Shapiro-Wilk test, t-test, and ROC analysis with AUC and Youden's index; p<0.05 was considered significant.
Results or Findings: Histopathology confirmed 21 metastatic and 17 benign LNs. Metastatic LNs showed higher uptake (mean SUVmax 2.60, 95% CI 1.91-3.29) than benign LNs (0.98, 95% CI 0.81-1.16; p<0.001), with an AUC of 0.852. An SUVmax cutoff of ≥1.56 yielded a specificity of 100% (17/17), sensitivity of 66.7% (14/21), PPV of 100% (14/14), NPV of 70.8% (17/24), and accuracy of 81.6% (31/38). Lower thresholds improved sensitivity but markedly reduced specificity. Subgroup analysis showed a trend toward higher uptake of metastatic LNs in invasive lobular carcinomas (ILC, n=5, mean SUVmax 3.61, 95% CI 1.33-5.89) compared to invasive ductal carcinomas (IDC, n=16, mean SUVmax 2.29, 95% CI 1.59-2.98; p=0.087).
Conclusion: 18F-FES-PET/MRI allows reliable LN characterization in ER+ BC. An SUVmax cutoff of ≥1.56 offers excellent specificity and overall accuracy, with higher uptake trends in lobular compared to ductal carcinoma.
Limitations: Retrospective, single-center design, and limited sample size.
Funding for this study: OeNB Anniversary Fund AB18207ONB
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: EK Nr. 510/2009