Fibroblast Activation Protein Inhibitor Research Articles

Abstract P005: Fibroblast Activation Protein (FAP)-targeted radioligand therapy as a promising treatment for glioblastoma

Abstract Introduction: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The 5-year survival rate is only 4% despite the current standard treatment approaches of surgery, chemotherapy, and radiation. Fibroblast Activation Protein (FAP)-targeted radioligand therapy (RLT) has emerged as a potential alternative to traditional radiation methods. FAP is a protein highly expressed in Cancer-Associated Fibroblasts (CAFs) and on GBM cells. It can be targeted by radiolabeled molecules for selective tumor irradiation, to enhance treatment precision and reduce damage to healthy tissue. Here we evaluated the relevance of FAP inhibitor 46 (FAPi-46) as a molecular probe for Radioligand Therapy (RLT) in GBM models. Methods: U87MG, a human GBM cell line shown to express human FAP and SB28, a murine GBM cell line engineered to express murine FAP were used as GBM models. NSG and C57BL6J mice were, respectively, inoculated with U87MG and SB28 cells subcutaneously. Tumor growth was evaluated by computed tomography (CT). FAP expression was assessed by 68Ga-FAPi-46 PET imaging when tumors reached around 100 mm3 prior to treatment. Mice were subsequently randomized into 4 groups: (1) vehicle, (2) 5 mg/kg temozolomide (TMZ), (3) 60 kBq 225Ac-FAPi-46, and (4) 5 mg/kg TMZ and 60 kBq 225Ac-FAPi-46. Dose of TMZ and 225Ac-FAPi-46 were increased for the SB28 study. Overall survival was tracked. Blood was collected 24h before, after, and 7 days after RLT treatment to assess blood toxicity. Tumor were resected 24h after RLT treatment to further evaluate DNA-damage. Results: Our results show that combining TMZ with 225Ac-FAPi-46 successfully delays tumor progression and extends survival in immunocompromised mice bearing subcutaneous human U87MG GBM tumors. In the SB28 GBM model neither TMZ nor a single dose of FAPi-RLT alone affected tumor growth or survival, confirming its in vivo resistance to both chemotherapy and radiation. However, by adapting the 225Ac-FAPi-46-RLT regimen, we observed a significant reduction in tumor volume and an increase in survival in immunocompetent mice. These results suggest that higher doses of 225Ac-FAPi-46-RLT can overcome resistance in this model. Conclusion: In conclusion, our study shows that 225Ac-FAPi-46-RLT could be an effective treatment for GBM, with positive results across different tumor models. To further investigate the efficacy of FAP-targeted RLT for GBM, we have initiated an evaluation of immune cell infiltration within subcutaneous SB28 tumors. Using immunohistochemistry, RNA sequencing, and flow cytometry, ongoing studies will characterize the immunogenic response induced by RLT in this GBM model. Citation Format: Pauline Jeanjean, Rachel Dove, Ines Camille Azrour, Samantha Kwock, Sarah Taylor, Sarina Smolev, Johannes Czernin, Giuseppe Carlucci, David Nathanson, Christine Mona, Elie Besserey-Offroy. Fibroblast Activation Protein (FAP)-targeted radioligand therapy as a promising treatment for glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P005

Autoradiography of Intracerebral Tumours in the Chick Embryo Model: A Feasibility Study Using Different PET Tracers.

In addition to rodent models, the chick embryo model has gained attention for radiotracer evaluation. Previous studies have investigated tumours on the chorioallantoic membrane (CAM), but its value for radiotracer imaging of intracerebral tumours has yet to be demonstrated. Human U87 glioblastoma cells and U87-IDH1 mutant glioma cells were implanted into the brains of chick embryos at developmental day 5. After 12-14days of tumour growth, blood-brain-barrier integrity was evaluated in vivo using MRI contrast enhancement or ex vivo with Evans blue dye. The tracers O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) (n = 5), 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine ([18F]FDOPA) (n = 3), or [68Ga] labelled quinoline-based small molecule fibroblast activation protein inhibitor ([68Ga]FAPI-46) (n = 4) were injected intravenously if solid tumours were detected with MRI. For time-activity curves for [18F]FET, additional micro PET (µPET) was performed. The chick embryos were sacrificed 60min post-injection, and cryosections of the tumour-bearing brains were produced and evaluated with autoradiography and immunohistochemistry. Intracerebral tumours were produced with a 100% success rate in viable chick embryos at the experimental endpoint. However, 52% of chick embryos (n = 85) did not survive the procedure to embryonic development day 20. For the evaluated radiotracers, the tumour-to-brain ratios (TBR) derived from ex vivo autoradiography, as well as the tracer kinetics derived from µPET for intracerebral chick embryo tumours, were comparable to those previously reported in rodents and patients: the TBRmean for [18F]FET was 1.69 ± 0.54 (n = 5), and 3.8 for one hypermetabolic tumour and < 2.0 for two isometabolic tumors using [18F]FDOPA, with a TBRmean of 1.92 ± 1,11 (n = 3). The TBRmean of [68Ga]FAPI-46 for intracerebral chick embryo tumours was 19.13 ± 0.64 (n = 4). An intact blood-tumour barrier was observed in one U87-MG tumour (n = 5). Radiotracer imaging of intracerebral tumours in the chick embryo offers a fast model for the evaluation of radiotracer uptake, accumulation, and kinetics. Our results indicate a high comparability between intracerebral tumour imaging in chick embryos and xenograft rodent models or brain tumour patients.

False-Positive FAPI Expression in Benign Breast Adenosis.

Breast adenosis is a benign glandular proliferative disorder. Due to its imaging similarities with other malignant breast lesions, differentiating adenosis from other invasive carcinomas of the breast poses a diagnostic challenge. Fibroblast activation protein inhibitor (FAPI) expression is observed in various benign and malignant lesions, increasing the risk of false-positive results. We present a case of FAPI-avid benign breast adenosis in a patient with adrenal adenocarcinoma in 68Ga-FAPI-46 PET/CT.

Monomeric or Homodimer Conjugates of Fibroblast Activation Protein Inhibitor and Cyanine 7 Bearing a Meso-Chloride as Near-Infrared Fluorescence Probes: Design, Synthesis, and Comparative In Vivo Imaging of Distinct Breast Cancer Subtypes.

Intraoperative fluorescence navigation can illuminate the tumor, directing surgeons to accurately achieve negative margins, which not only reduces recurrence but also minimizes the incidence of complications. Herein, we developed two near-infrared fluorescent probes FAPI-Cy7-Cl (Emmax = 820 nm) and (FAPI)2-Cy7-Cl (Emmax = 823 nm) with prolonged tumor retention (>72 h) and high target-to-background ratios (up to 4.5) based on the conjugation of pan-cancer targeted fibroblast activation protein inhibitor (FAPI) and the "tumor-seeking" Cyanine 7 bearing a meso-chloride and a cyclohexenyl skeleton (Cy7-Cl). Specifically, FAPI-Cy7-Cl exhibited superior imaging performance in both estrogen receptor α positive breast cancer (MCF-7) and triple-negative breast cancer (TNBC) (MDA-MB-231) subtypes in mouse models. Notably, in the MDA-MB-231 tumor-bearing model, the tumor-to-liver ratio (T/L) of FAPI-Cy7-Cl increased rapidly after 2 h postinjection, reaching nearly 4.5 at 48 h, making it an optimal imaging probe for guiding TNBC surgery resection.

18F-FAPI-42 PET/CT and 18F-FDG PET/CT in Patients with Malignant Digestive System Neoplasms: A Head-to-Head Comparative Study.

Radionuclide-labeled fibroblast activation protein inhibitor (FAPI) is an emerging tumor tracer. We sought to assess the uptake and diagnostic performance of 18F-FAPI-42 PET/CT compared with simultaneous 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG) PET/CT in primary and metastatic lesions in patients with malignant digestive system neoplasms and to determine the potential clinical benefit. Forty-two patients (men = 30, women = 12, mean age = 56.71 ± 13.26years) who underwent 18F-FDG PET/CT and 18F-FAPI-42 PET/CT simultaneously for diagnosis, staging, and restaging were enrolled. Quantitative data, including standardized uptake value (SUV), tumor-to-liver ratio (TLR), and tumor-to-blood pool ratio (TBR), were analyzed. Two independent readers performed a visual assessment of lesion number and location on PET/CT images. Interobserver agreement between two examinations was calculated using Cohen's kappa (κ). Primary tumor locations included the liver (n = 20), stomach (n = 9), pancreas (n = 5), and intestine (n = 10). More intense 18F-FAPI-42 uptake and higher tumor-to-background contrast were detected in most primary and metastatic lesions compared with 18F-FDG, contributing to improved diagnostic accuracy ranging from 95.24% to 100%. Moreover, additional lesions showing 18F-FAPI-42 uptake in primary, locoregional and distant metastatic lesions were visualized, especially in multiple liver and peritoneal metastases. Patient-based interobserver agreement varied from moderate to strong, with suboptimal outcomes observed in primary tumors (κ = 0.441, P = 0.01) and preferable results derived from metastatic liver and bone lesions (κ = 1 and 0.896, both P < 0.01). 18F-FAPI-42 PET/CT resulted in modified treatment strategies for 40.48% (17/42) of patients, while 18F-FDG PET/CT led to altered therapeutic regimens in only 4.8% (2/42) of patients. In selected patients with malignant digestive system neoplasms, our study shows that 18F-FAPI-42 PET/CT is a promising alternative for assessing primary tumors and metastases and aiding staging, restaging, and decision-making, with higher uptake and better lesion visualization compared with 18F-FDG. Additionally, it may shed light into the treatment selection and response assessment for FAP-targeted therapy or immunotherapy.

Glycyrrhizinate Monoammonium Cysteine-Loaded Lipid Nanoparticles Allow for Improved Acute Liver Injury Therapy.

Background: Acute liver injury (ALI) is a prevalent and potentially lethal condition globally, where pharmacotherapy plays a vital role. However, challenges such as rapid drug excretion and insufficient concentration at hepatic lesions often impede the treatment's effectiveness. Methods: We successfully prepared glycyrrhizinate monoammonium cysteine (GMC)-loaded lipid nanoparticles (LNPs) using high-pressure homogenization. The characterization and safety of the LNPs were measured using electrophoretic light scattering (ELS), transmission electron microscopy (TEM), dynamic light scattering (DLS), cytotoxicity assays, and hemolysis tests. The distribution of LNPs in mice was explored using fluorescence labeling methods. The encapsulation efficiency of LNP-GMC was detected using High-Performance Liquid Chromatography (HPLC), and its slow-release effect on GMC was assessed through dialysis. The therapeutic effects of LNP-GMC and pure GMC on the ALI model were evaluated using fibroblast activation protein inhibitor (FAPI) PET imaging, blood biochemical indicators, and liver pathology slices. Results: The encapsulation of GMC in LNPs enhances drug stability and prolongs its hepatic retention, significantly improving its bioavailability and sustained release within the liver. This study also explores the expression of fibroblast activation protein (FAP) in ALI, employing 68Ga-FAPI PET/CT imaging for effective differentiation and assessment of liver injury. Conclusions: Our results suggest that LNPs offer an enhanced therapeutic approach for ALI treatment, reducing the required drug dosage, and 68Ga-FAPI PET/CT imaging provides a novel method for diagnosis and treatment assessment. This study contributes valuable insights into the utilization of LNPs in liver disease treatment, presenting a promising direction for future clinical applications.

CTR-FAPI PET Enables Precision Management of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but current clinical practice fails to localize the disease in 29% to 60% of patients. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]fluorodeoxyglucose ([18F]FDG) PET-CT in 50 patients with MTC. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, P = 0.0002). This improved detection was attributed to increased tumor uptake (maximum standardized uptake value = 11.71 ± 9.16 vs. 2.55 ± 1.73, P < 0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared with [18F]FDG (96.7% vs. 43.3%, P < 0.0001). Notably, the management of 32% of patients was altered following [68Ga]Ga-CTR-FAPI PET-CT, and the surgical plan was changed for 66.7% of patients. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared with [18F]FDG PET-CT, enabling precision management of patients with MTC. Significance: In this first-in-class clinical trial of CTR, [68Ga]Ga-CTR-FAPI demonstrated an improved patient-based detection rate (98%), tumor uptake (maximum standardized uptake value = 11.71 ± 9.16), and pathology-validated diagnostic accuracy (96.7%) compared with the currently approved method in MTC treatment. It directly altered management in 32% of patients, enabling precision diagnosis and management of MTC. See related commentary by Witney, p. 264.

Localized InVivo Prodrug Activation Using Radionuclides.

Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof of principle, we tested whether this strategy of radionuclide-induced drug engagement for release (RAiDER) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing off-target exposure to activated chemotherapy. Methods: We screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule-destabilizing monomethyl auristatin E (MMAE) caged by a radiation-responsive phenyl azide, and we interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using the fibroblast activation protein inhibitor (FAPI) agents [99mTc]Tc-FAPI-34 and [177Lu]Lu-FAPI-04 and the prostate-specific membrane antigen (PSMA) agent [177Lu]Lu-PSMA-617, combined with caged MMAE or caged exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER. Results: RAiDER efficiency varied by 70-fold across radionuclides (99mTc > 111In > 177Lu > 64Cu > 32P > 68Ga > 223Ra > 18F), yielding up to 320 nM prodrug activation/Gy of exposure from 99mTc. Computational simulations implicated low-energy electron-mediated free radical formation as driving prodrug activation. Radionuclide-activated caged MMAE restored the prodrug's ability to destabilize microtubules and increased its cytotoxicity by up to 2,600-fold that of the nonactivated prodrug. Mice treated with [99mTc]Tc-FAPI-34 and caged MMAE accumulated concentrations of activated MMAE that were up to 3,000 times greater in tumors than in other tissues. RAiDER with [99mTc]Tc-FAPI-34 or [177Lu]Lu-FAPI-04 delayed tumor growth, whereas monotherapies did not (P < 0.003). Clinically guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug. Conclusion: This proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and can potentially improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biologic and therapeutic responses.

18F-FAPI-42 PET/CT for preoperatively identifying intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

Accurately differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC) is essential for therapeutic decision-making. This study aimed to explore the value of Fluor 18 (18F)-conjugated fibroblast-activation protein inhibitor (FAPI-42) positron emission tomography-computed tomography (PET/CT) in distinguishing HCC from ICC preoperatively. Patients with suspected intrahepatic lesions who underwent 18F-FAPI-42 PET/CT were retrospectively assessed and placed into an HCC group and an ICC group based on postoperative pathology. Clinical indicators and PET/CT metabolic parameters were documented. Univariate and multivariate logistic regression analyses identified the independent predictive factors. The receiver operating characteristic curve and the area under the receiver operating curve (AUC) were used to determine the diagnostic efficacy. A total of 48 patients (age 55.4±10.8 years; 35 males and 13 females), including 28 in the HCC and 20 in the ICC group, were included. Univariate analysis revealed significant differences in clinical indicators such as gender, platelet count, and hepatitis B surface antigen, carbohydrate antigen 19-9 (CA19-9), and alpha fetoprotein (AFP) levels between the groups (P<0.05). Metabolic parameters including the maximum standardized uptake value (SUVmax), the total lesion-FAPI (TL-FAPI), and the target-to-background ratio (TBR) were statistically different between groups (P<0.01), and patients with ICC had higher values than those with HCC, while the FAPI tumor volume (FAPI-TV) was not statistically different (P>0.05). Multivariate binary logistic regression analysis identified the SUVmax (P=0.003) as an independent predictor for ICC, and the AUC of the regression-based diagnostic model for predicting ICC was 0.914 at an optimal cutoff value of 12.13, with a sensitivity of 85.0% and a specificity of 89.3%. SUVmax is an independent predictor for ICC. With the optimal cutoff value of 12.13, 18F-FAPI-42 PET/CT indicates good diagnostic efficacy in distinguishing between HCC and ICC.

Fibroblast activation protein inhibitors positron emission tomography/computed tomography: Review of the literature

Positron emission tomography/computed tomography (PET/CT) with radiolabeled fibroblast activation protein inhibitors (FAPI) is an increasingly relevant molecular diagnostic image in oncology given the high expression of FAP in cancer associated fibroblast, being present in almost 90% of the epithelial carcinomas, which allows imaging with excellent diagnostic performance and can also become a therapeutic strategy. This review summarizes the literature on FAPI-PET/CT for the cancer evaluation and compares it in some scenarios with the 18F-Fluorodeoxyglucose PET/CT.

177Lu Radiolabeled Polydopamine Decorated with Fibroblast Activation Protein Inhibitor for Locoregional Treatment of Glioma.

Radionuclide therapy is expected to be a powerful tool for glioma treatment. Here, we introduce a novel nuclear nanomedicine based on polydopamine (PDA), incorporating fibroblast activation protein inhibitor (FAPI) and macrocyclic chelator (DOTA) for specific cancer targeting and 177Lu labeling. The synthesized nanoradiopharmaceutical, 177Lu-DOTA-PEG-PDA-FAPI, exhibits good stability in serum, saline and PBS over 5 days. 177Lu-DOTA-PEG-PDA-FAPI shows efficient specific uptake and internalization when incubated with U87MG cells. In vivo distribution visualized prominent accumulation and long retention ability of 177Lu-DOTA-PEG-PDA-FAPI at tumor sites after local administration. Moreover, 177Lu-DOTA-PEG-PDA-FAPI has satisfactory antitumor ability without apparent toxic and side effects observed from therapy assay and H&E staining. This study highlights the feasibility of using PDA as a nanocarrier for glioma endoradiotherapy by targeting fibroblast activation protein.

Semiquantitative muscle parameters derived from FAPI and FDG PET/CT in evaluating sarcopenia among patients with malignant tumors.

The objective of this study is to explore and compare the potential utility of fibroblast activation protein inhibitor (FAPI) and fluorodeoxyglucose PET/computed tomography (CT) in assessing sarcopenia among patients with malignant tumors. A retrospective analysis was conducted on 127 patients with histologically confirmed malignant tumors who underwent both 18F/68Ga-FAPI and fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT scans. Clinical characteristics and PET/CT parameters of maximum and mean standard uptake value (SUVmax and SUVmean) of muscle at the 3rd lumbar (L3) level were reviewed. Skeletal muscle area at the L3 level was measured, and skeletal muscle index was calculated to determine sarcopenia. The association between sarcopenia and PET/CT parameters was analyzed. The incidence of sarcopenia was 41.7% among these 127 patients. Higher age, male, lower BMI, lower SUVmax and SUVmean of muscle from 18F/68Ga-FAPI PET/CT, and lower SUVmax of muscle from 18F-FDG PET/CT were correlated with a higher prevalence of sarcopenia (P < 0.05). Besides, no significant differences in SUVmax and SUVmean of muscle were noted between 18F-FAPI and 68Ga-FAPI groups. The best cutoff value of SUVmax of muscle from 18F/68Ga-FAPI PET/CT was 1.17, yielding the area under the curve (AUC) of 0.764 and sensitivity and specificity of 74.3% and 71.7%, while the optimal cutoff value of SUVmax of muscle from 18F-FDG PET/CT was 0.76, with an AUC of 0.642 and sensitivity and specificity of 36.5% and 86.8%, respectively. Patients with sarcopenia exhibit decreased muscle uptake of FAPI and fluorodeoxyglucose. FAPI PET/CT emerges as a more valuable tool for sarcopenia assessment in patients with malignant tumors compared to fluorodeoxyglucose PET/CT.

Cardiovascular positron emission tomography imaging of fibroblast activation: A review of the current literature.

Fibrosis is one of the key healing responses to injury, especially within the heart, where it helps to maintain structural integrity following acute insults such as myocardial infarction. However, if it becomes dysregulated, then fibrosis can become maladaptive, leading to adverse remodelling, impaired cardiac function and heart failure. Fibroblast activation protein is exclusively expressed by activated fibroblasts, the key effector cells of fibrogenesis, and has a unique extracellular domain that is an ideal ligand for novel molecular imaging probes. Fibroblast activation protein inhibitor (FAPI) radiotracers have been developed for positron emission tomography (PET) imaging, demonstrating high selectivity for activated fibroblasts across a range of different pathologies and disparate organ systems. In this review, we will summarise the role of fibroblast activation protein in cardiovascular disease and how FAPI radiotracers might improve the assessment and treatment of patients with cardiovascular diseases.

Comparison of [18F]FAPI-42 and [18F]FDG PET/CT in the evaluation of systemic vasculitis.

The role of fibroblast activation protein (FAP)-targeted imaging in systemic vasculitis is currently unclear. We aimed to evaluate the clinical value of fluorine-18-labeled FAP inhibitor 42 ([18F]FAPI-42) in patients with systemic vasculitis and to compare with [18F]fluorodeoxyglucose (FDG) imaging. Patients with systemic vasculitis who underwent dual-tracer PET/CT([18F]FDG and [18F]FAPI) imaging from September 2020 to March 2022 were retrospectively analyzed. Positive lesions are defined as vascular/extravascular lesions with increased tracer uptake above surrounding background, which cannot be attributed to the physiologic biodistribution of the radiotracer. The vascular/extravascular lesion detection rate and semiquantitative values (SUVmax, TBRblood and TBRliver) of [18F]FAPI and [18F]FDG were compared, and the correlation between the extent and range of tracer uptake and levels of inflammatory markers was investigated. Thirty patients (13 males and 17 females; mean age, 52.5 ± 17.2 years) with systemic vasculitis were included (17 large vessel vasculitis, 10 anti-neutrophil cytoplasmic antibody-associated vasculitis, 2 Behcet's disease and 1 polyarteritis nodosa). [18F]FDG PET/CT had positive findings in 93.3% (28/30) of patients, while [18F]FAPI PET/CT had positive findings in all patients (100%, P = 0.500). Compared with [18F]FDG PET/CT, [18F]FAPI PET/CT detected more lesions (161/168 vs. 145/168, P = 0.005), and more extensive vascular involvement in 60% (18/30) of patients. Although SUVmax did not differ significantly between [18F]FAPI and [18F]FDG (median, 5.94 vs. 5.46, P = 0.517), [18F]FAPI had higher TBRliver (median, 9.59 vs. 3.15, P < 0.001) and TBRblood (median, 5.45 vs. 4.20, P = 0.006). The total number of positive lesions in FAPI PET/CT show a moderate correlation with erythrocyte sedimentation rate (rs =0.478, P = 0.008) and C-reactive protein (rs =0.486, P = 0.006). After treatment, follow-up FAPI PET/CT of 6 patients showed decreased SUVmax, TBR and number of detected lesions, paralleling the clinical remission. [18F]FAPI PET/CT imaging is a promising imaging modality for the diagnosis and therapeutic monitoring of systemic vasculitis.

Recent advances in nuclear medicine and their role in inflammatory arthritis: focus on the emerging role of FAPI PET/CT

AbstractImaging molecular processes associated with inflammatory disease has been revolutionized by hybrid imaging using positron emission tomography/computed tomography (PET/CT). PET/CT visualizes metabolic activity as well as protein expression and provides a comprehensive whole-body evaluation. It has the potential to reveal inflammation prior to detection of structural changes in inflammatory joint diseases. FAP is a type II transmembrane glycoprotein overexpressed not only in the stroma of tumors but also in the fibrotic processes of certain immune-mediated disorders. The recent introduction of fibroblast activation protein inhibitors (FAPI) labeled by positron emitters and thus suitable for PET/CT allows to investigate FAP expression in vivo. This review will focus on the use of FAPI-PET/CT for the diagnosis and evaluation of treatment response in inflammatory joint diseases.

Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents.

The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [18F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.

Emerging Radiopharmaceuticals in Pet Imaging for Mesothelioma: A Review of [18F]FDG Alternatives.

Mesothelioma is a malignant tumor associated primarily with asbestos exposure, characterized by an aggressive nature and poor prognosis. Accurate diagnosis, staging, and monitoring of therapeutic response are crucial for effective patient management. Along with a computed tomography (CT) scan, fluorodeoxyglucose labeled with fluorine-18 ([18F]FDG) positron emission tomography (PET) is commonly used in mesothelioma evaluation. However, it has some limitations, including lower sensitivity after pleurodesis and poor accuracy for involved lymph node evaluation. Thus, there is the need to explore other agents. The aim of the present review is to analyze the current literature on the use of alternative radiopharmaceuticals for PET imaging in patients with mesothelioma. A comprehensive search of scientific databases (PubMed, Scopus, and Web of Science) for studies published in the last decade was performed by using the following keywords: "mesothelioma" AND "PET" AND "PET/CT" "radiopharmaceuticals", "[18F]FDG alternatives". Articles focused solely on [18F]FDG, non-English publications or preclinical studies, reviews, meeting abstracts, letters to the editors, and editorials were excluded. A qualitative assessment was made by using the Critical Appraisal Skills Programme (CASP) checklist for diagnostic test studies, when applicable. In total, 14 papers were selected; in seven articles more than five patients were enrolled, while the other seven were only clinical cases (enrolling up to two subjects). [18F]/gallium-68 ([68Ga])-labeled fibroblast activation protein inhibitor (FAPI) compounds, [18F]Fluorothymidine ([18F]FLT), methionine labeled with carbon-11 ([11C]MET), and fluoromisonidazole labeled with fluorine-18 ([18F]FMISO) PET/CT were the alternative agents used most often. In 12 articles, [18F]FDG PET/CT was used as a comparator imaging modality. Detection rate of [18F]FDG was similar to the other radiopharmaceuticals ([68Ga]/[18F]-labeled FAPI compounds, [18F]FLT, [18F]FMISO, [11C]MET, and [68Ga]-Pentaxifor), although radiolabeled FAPI seems to exhibit a higher diagnostic performance. [18F]FDG is still a valuable agent in patients with mesothelioma. However, radiolabeled FAPI appears to be promising and its theranostic properties should therefore be further assessed.

Exploring the FAP-Targeted Therapeutics for Adrenocortical Carcinoma: Choosing the Right Track.

Metastatic or recurrent adrenocortical carcinoma is a potentially lethal malignancy, presenting significant challenges in disease management owing to absence of effective systemic treatments. Significantly diminished survival rates necessitate rapid identification of specific molecules for the development of targeted therapeutics. Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts have been a major breakthrough causing a paradigm shift in targeted theranostics focusing on the tumor microenvironment. The effectiveness of various FAP inhibitors (FAPis) and FAP targeting peptide has been extensively documented in diverse clinical investigations. We have evaluated 3 molecules, that is, DOTA.SA.FAPi (SA.FAPi), FAPi46, and FAP2286, as potential theranostic probes for adrenocortical carcinoma.

Feasibility of Early 68 Ga-FAP-2286 PET Imaging: A Case Study.

Fibroblast activation protein (FAP) has emerged as a promising molecular target for diagnostic and therapeutic strategies. Previous research, including our own study and other published reports, has highlighted the potential of FAP inhibitors labeled with 68 Ga as effective diagnostic radiopharmaceuticals. In this study, we present a comparative analysis of early and late PET/CT scans, using 68 Ga-FAP-2286, for the detection of tumor lesions in a patient with metastatic breast adenocarcinoma.

O09 Correlation between Fibroblast Activation Protein inhibitor (99mTc-FAPi/SPECT) and histology in patients submitted to Retroperitoneal Lymph Node Dissection (RPLND) with residual post-chemotherapy disease in Non-Seminomatous Germ Cell Tumors (NSGCT)

O09 Correlation between Fibroblast Activation Protein inhibitor (99mTc-FAPi/SPECT) and histology in patients submitted to Retroperitoneal Lymph Node Dissection (RPLND) with residual post-chemotherapy disease in Non-Seminomatous Germ Cell Tumors (NSGCT)