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Background: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2, labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. Methods: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were evaluated in PC3 xenografts. Biodistribution studies of [68Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. Results: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [177Lu]Lu-DOTAGA.(SA.FAPi)2 was retained longer in CAFs. [68Ga]Ga-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.(SA.FAPi)2 displayed elevated lipophilicity and affinity for human serum proteins compared to [68Ga]Ga-DOTA.SA.FAPi and [177Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [68Ga]Ga-DOTAGA.(SA.FAPi)2 within 3 h compared to [68Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [68Ga]Ga-DOTAGA.(SA.FAPi)2 versus [68Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [177Lu]Lu-DOTAGA.(SA.FAPi)2 maintained a significant tumor uptake even after 96 h p.i. compared to [177Lu]Lu-DOTA.SA.FAPi. Conclusions: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.

This systematic review aims to examine the safety and efficacy of fibroblast activation protein inhibitor (FAPI) radioligand therapy (RLT) for various epithelial neoplasms. PubMed, Web of Science, and Scopus databases were searched up to Jan 4, 2025, for studies involving FAPI RLT in various cancers. Data extraction focused on exploring safety and efficacy of FAPI RLT. Overall, 27 studies involving a total of 144 patients who received FAPI RLT were included in this systematic review. [ Lu]Lu-FAPI was employed in 21 studies, with 225 cycles administered to 95 patients at a median dose of 6.8 GBq/cycle. Six non-randomized clinical investigations using [ Lu]Lu-FAPI reported disease control rates ranging from 18.2% to 83.3%. Only three studies documented a cumulative total of six patients who experienced grade 3 or 4 toxicity post [ Lu]Lu-FAPI RLT. Of 16 case reports utilizing [ Lu]Lu-FAPI, nine achieved disease control across various cancer types, with no reported adverse events. Four studies employed [ Y]Y-FAPI, totaling 103 cycles in 42 patients at a median dose of 6.7 GBq/cycle. Three non-randomized clinical investigations reported disease control rates of 50% to 82%, with two studies documenting eight high-grade toxicity events. Furthermore, a successful administration of [ Y]Y-FAPI was employed in a single reported case involving multiple primary neoplasms with no reported adverse events. However, the patient did not achieve disease control post [ Y]Y-FAPI. A cohort study utilized 53 [ Bi]Bi-FAPI-46 injections following a fractionated dose regimen in six cancer patients, achieving a 33.3% disease control rate without reported adverse events. One case report described dual radionuclide therapy using two cycles with a cumulative 20 GBq [ Sm]Sm-FAPI and a third 8 GBq [ Y]Y-FAPI cycle in a lung cancer patient, resulting in stable disease for eight months. FAPI RLT is a promising and safe therapeutic agent in oncology, with potential benefits achieved on short-term basis. However, its long-term efficacy and safety require further research with larger, controlled studies, considering the currently observed variations in patient populations, cancer types, and methodologies within reviewed studies.

Chuanyin Sun,1,* Haopeng Ni,2,* Mengdi Jiang,1 Guolin Wang,3 Xinhui Su,3 Zhenfeng Liu3 1Department of Rheumatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People’s Republic of China; 2Zhejiang University School of Medicine, Hangzhou, Zhejiang, 3100058, People’s Republic of China; 3Department of Nuclear Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenfeng Liu; Xinhui Su, Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University, #79 Qingchun Road, Hangzhou, Zhejiang, 310003, People’s Republic of China, Email zhenfeng19792003@zju.edu.cn; suxinhui@zju.edu.cnAbstract: Kimura’s disease is a rare, chronic inflammatory disorder characterized by subcutaneous nodules, eosinophilia, and elevated serum IgE levels. It commonly affects young Asian males and typically presents in the head and neck region. Diagnosis is confirmed via histopathological examination, while treatment options include corticosteroids, surgery, and radiotherapy. [18F]AlF-NOTA-FAPI-04 PET/CT demonstrated superior imaging, with clearer background and higher target-to-background ratio, highlighting lesions with higher SUV values and greater specificity for fibroblast activity. Compared to 18F-FDG PET/CT, which is limited by nonspecific uptake in inflammatory tissues, [18F]AlF-NOTA-FAPI-04 PET/CT offers superior sensitivity and specificity in visualizing fibroblast activation. These advantages not only improve diagnostic accuracy in Kimura’s disease but may also have broader implications for other eosinophilic or inflammatory disorders sharing similar clinical features. This technique improves diagnostic accuracy, facilitates treatment planning, and may guide the development of future treatment.Keywords: kimura’s disease, FAPI, PET

Purpose 68  Ga-FAPI (fibroblast activation protein inhibitor) is a rapidly evolving and highly promising radiotracer for PET/CT imaging, presenting excellent results in a variety of tumor entities, particularly in epithelial carcinomas. This retrospective analysis sought to evaluate the potential and impact of FAPI-PET/CT in rare cancer diseases with respect to improvement in staging and therapy, based on tracer uptake in normal organs and tumors. Material and methods Fifty-five patients with rare tumor entities, defined by a prevalence of 1 person out of 2000 or less, received a 68  Ga-FAPI-PET/CT scan. Fourteen women and 41 men (median age 60) were included within the following subgroups: cancer of unknown primary ( n  = 10), head and neck cancer ( n  = 13), gastrointestinal and biliary-pancreatic cancer ( n  = 17), urinary tract cancer ( n  = 4), neuroendocrine cancer ( n  = 4), and others ( n  = 7). Tracer uptake was quantified by standardized uptake values SUVmax and SUVmean and the tumor-to-background ratio (TBR) was determined (SUVmax tumor/SUVmean organ). Results In 20 out of 55 patients, the primary tumor was identified and 31 patients presented metastases ( n  = 88), characterized by a high mean SUVmax in primary (10.1) and metastatic lesions (7.6). The highest uptake was observed in liver metastases ( n  = 6) with a mean SUVmax of 9.8 and a high TBR of 8.7, closely followed by peritoneal carcinomatosis ( n  = 16) presenting a mean SUVmax of 9.8 and an excellent TBR of 29.6. In terms of the included subgroups, the highest uptake regarding mean SUVmax was determined in gastrointestinal and biliary-pancreatic cancer with 9.8 followed closely by urinary tract cancer with 9.5 and head and neck cancer (9.1). Conclusion Due to excellent tumor visualization and, thereby, sharp contrasts in terms of high TBRs in primary and metastatic lesions in different rare malignancies, 68  Ga-FAPI-PET/CT crystallizes as a powerful and valuable imaging tool, particularly with respect to epithelial carcinomas, and therefore an enhancement to standard diagnostics imaging methodologies. The realization of further and prospective studies is of large importance to confirm the potential of FAP imaging in oncology.

Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides 177Lu and 225Ac. This was improved with the dimer DOTAGA.(SA.FAPi)2, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)2 and DOTAGA.Glu.(FAPi)2. were synthesized and quantitatively radiolabeled with 68Ga, 90Y, 177Lu and 225Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [225Ac]Ac-DOTAGA.Glu.(FAPi)2 in PBS. In vitro affinity studies resulted in subnanomolar IC50 values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [natLu]Lu-DOTAGA.Glu.(FAPi)2. In a first proof-of-principle patient study (medullary thyroid cancer), [177Lu]Lu-DOTAGA.Glu.(FAPi)2 was compared to [177Lu]Lu-DOTAGA.(SA.FAPi)2. High uptake and long tumor retention was observed in both cases, but [177Lu]Lu-DOTAGA.Glu.(FAPi)2 significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)2 showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [225Ac]Ac-DOTAGA.Glu.(FAPi)2 appear promising for translational application in patients.

Purpose Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64 Cu and 225 Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter ( 177 Lu)-labelled FAPI-46 and alpha-emitter ( 225 Ac)-labelled FAPI-46 in pancreatic cancer models. Methods PET scans (1 h post injection) were acquired in PANC-1 xenograft mice ( n  = 9) after the administration of [ 18 F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 were evaluated in the xenograft model (total n  = 12). For the determination of treatment effects, [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq ( n  = 6), 10 MBq ( n  = 6), 30 MBq ( n  = 6), control ( n  = 4) for [ 177 Lu]FAPI-46, and 3 kBq ( n  = 3), 10 kBq ( n  = 2), 30 kBq ( n  = 6), control ( n  = 7) for [ 225 Ac]FAPI-46. Tumour sizes and body weights were followed. Results [ 18 F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [ 177 Lu]FAPI-46 were relatively slow but lasted longer than those of [ 225 Ac]FAPI-46. Conclusion This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

IntroductionFibroblast activation protein-α (FAPα) is overexpressed on cancer-associated fibroblasts in approximately 90% of epithelial neoplasms, representing an appealing target for therapeutic and molecular imaging applications. [68 Ga]Ga-labelled radiopharmaceuticals—FAP-inhibitors (FAPI)—have been developed for PET. We systematically reviewed and meta-analysed published literature to provide an overview of its clinical role.Materials and methodsThe search, limited to January 1st, 2018–March 31st, 2021, was performed on MedLine and Embase databases using all the possible combinations of terms “FAP”, “FAPI”, “PET/CT”, “positron emission tomography”, “fibroblast”, “cancer-associated fibroblasts”, “CAF”, “molecular imaging”, and “fibroblast imaging”. Study quality was assessed using the QUADAS-2 criteria. Patient-based and lesion-based pooled sensitivities/specificities of FAPI PET were computed using a random-effects model directly from the STATA “metaprop” command. Between-study statistical heterogeneity was tested (I2-statistics).ResultsTwenty-three studies were selected for systematic review. Investigations on staging or restaging head and neck cancer (n = 2, 29 patients), abdominal malignancies (n = 6, 171 patients), various cancers (n = 2, 143 patients), and radiation treatment planning (n = 4, 56 patients) were included in the meta-analysis. On patient-based analysis, pooled sensitivity was 0.99 (95% CI 0.97–1.00) with negligible heterogeneity; pooled specificity was 0.87 (95% CI 0.62–1.00), with negligible heterogeneity. On lesion-based analysis, sensitivity and specificity had high heterogeneity (I2 = 88.56% and I2 = 97.20%, respectively). Pooled sensitivity for the primary tumour was 1.00 (95% CI 0.98–1.00) with negligible heterogeneity. Pooled sensitivity/specificity of nodal metastases had high heterogeneity (I2 = 89.18% and I2 = 95.74%, respectively). Pooled sensitivity in distant metastases was good (0.93 with 95% CI 0.88–0.97) with negligible heterogeneity.ConclusionsFAPI-PET appears promising, especially in imaging cancers unsuitable for [18F]FDG imaging, particularly primary lesions and distant metastases. However, high-level evidence is needed to define its role, specifically to identify cancer types, non-oncological diseases, and clinical settings for its applications.

PurposeRenal fibrosis is a pathological state in the progression of chronic kidney disease. Early detection and treatment are vital to prolonging patient survival. Renal puncture examination is the gold standard for renal fibrosis, but it has several limitations. This study aims to evaluate the diagnostic performance of a novel PET radiotracer, [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04, which specifically images fibroblast activation protein (FAP) expression for renal fibrosis.MethodsAll patients underwent renal puncture before receiving [68Ga]Ga-FAPI-04 PET/CT imaging. They then underwent [68Ga]Ga-FAPI-04 PET/CT and immunochemistry examinations. The data obtained were analyzed.ResultsThe [68Ga]Ga-FAPI-04 PET/CT examination results demonstrated that almost all patients (12/13) exhibited increased radiotracer uptake. The maximum standardized uptake value (SUVmax) in patients with mild, moderate, and severe fibrosis was 3.92 ± 1.50, 5.98 ± 1.6, and 7.67 ± 2.23, respectively.ConclusionCompared with renal puncture examination, non-invasive imaging of FAP expression through [68Ga]Ga-FAPI-04 PET/CT quickly demonstrates bilateral kidney conditions with high sensitivity. [68Ga]Ga-FAPI-04 PET/CT can facilitate the evaluation of disease progression, diagnosis, and the development of a treatment plan.

Growing studies have recently reported on the promising application of radiolabeled-fibroblast activation protein inhibitors (FAPIs) as diagnostic and therapeutic agents in various oncological populations. To exclusively evaluate the current evidence on the diagnostic and therapeutic role of FAPI radiotracers in patients with breast cancer (BC), a narrative review of the available literature was performed. A search algorithm from PubMed/MEDLINE, based on the combination of “PET” OR “positron emission tomography” and “FAPI” and ”cancer”, with a last update in February 2022, was applied. From 233 identified articles, 33 studies conducted in BC patients and with available data on PET imaging or radiolabeled-FAPI therapy were finally considered, for a total of 191 patients. Despite some clinical and methodological heterogeneity among the reviewed articles, 68Ga-FAPI PET/CT emerges as a valuable diagnostic tool in BC patients both at staging and restaging, also demonstrating several technical advantages and an overall better performance than 18F-FDG, especially in histotypes with well-known low 18F-FDG avidity. Moreover, although with still limited clinical evidence in BC, radiolabeled FAPIs emerge as promising therapeutic agents in a theranostic perspective, increasing the possibility of more personalized treatments. From these results, future research directions on FAPI radiotracers application in BC patients are suggested.

68Ga and 177Lu‐labeled fibroblast activation protein inhibitor (FAPI) have been introduced for the diagnosis and treatment of multiple malignant and non‐malignant diseases. While several studies have examined the application of 68Ga‐FAPI in myocardial infarction (MI), research on the use of 177Lu‐FAPI for the treatment of MI is still scarce. In this study, we evaluated the effects of 68Ga‐FAPI and 177Lu‐FAPI in cardiac fibrosis after MI using permanent coronary artery ligation rat models. 68Ga‐FAPI‐04 effectively targeted fibroblasts within the MI area. Rats treated with 177Lu‐FAPI‐04 had a significant increase in left ventricular ejection fraction at 28 days post‐MI, with no obvious kidney or liver toxicity. Magnetic resonance imaging and histological analysis revealed a reduced fibrotic area in the 177Lu‐FAPI group. 177Lu‐FAPI‐04 exerted its therapeutic effect by suppressing activation and inducing apoptosis of fibroblasts. In summary, we demonstrated that 177Lu‐FAPI‐04 could effectively target FAP and eliminate activated fibroblasts after MI, thereby contributing to the development of new strategies for the treatment of MI. Our study evaluates the specific accumulation of 68Ga‐FAPI‐04 in infarcted hearts and suggests that treatment with 177Lu‐FAPI‐04 may enhance cardiac function by modulating fibroblast activation and apoptosis, thereby reducing cardiac fibrosis after myocardial infarction.