Fibroblast Activation Protein Inhibitor Research Articles

A comparative review of the application value of FAPI PET/CT and 18F-FDG PET/CT in lung cancer.

Fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) is a multimodal imaging technique that combines PET and CT, utilizing FAP inhibitors as radiotracers. Fibroblast activation protein, a serine protease highly expressed in many epithelial tumor-associated fibroblasts, plays a crucial role in tumor stroma formation and remodeling. Through the detection of FAP expression, FAPI PET/CT facilitates the diagnosis and staging of both benign and malignant pulmonary tumors. In contrast to traditional fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT focusing on glucose metabolism, FAPI PET/CT offers benefits such as enhanced specificity, reduced background noise, accelerated imaging speed, and decreased radiation exposure. This review provides an overview of the progress in applying FAPI PET/CT and 18F-FDG PET/CT in pulmonary malignancies and discusses current challenges and future prospects.

Initial clinical experience using 68Ga-FAPI-46 PET/CT for detecting various cancer types.

Numerous studies have shown that gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) positron emission tomography/computed tomography (PET/CT) scans would yield high intra-tumoral tracer uptake and low uptake in normal tissues as background, thus allowing for excellent visualization of lesions in the cancer microenvironment. This study set out to compare the suitability of novel 68Ga-FAPI-46 PET versus routine fluorine-18-fluorodeoxyglucose (18F-FDG) PET and other few cases of 68Ga-DOTATATE/68Ga-Pentixafor PET/CT for the assessment of different types of cancer. A retrospective analysis of 11 patients (6 males, 5 females; average age: 53 years, range: 10-58 years) with histopathologically confirmed, well-differentiated adenocarcinoma, medullar thyroid cancer (MTC), papillary thyroid carcinoma (PTC), cervical, gastric, glioblastoma multiform (GBM), colon, Ewing's sarcoma, and breast cancer was performed. These patients underwent PET/CT scans using four different radiotracers (9 18F-FDG, 11 68Ga- FAPI, 3 68Ga-DOTATATE, and 1 68Ga-Pentixafor). The patients' PET/CT images were visually evaluated for cancer detection, and analyzed semi-quantitatively through image- derived metrics, such as target-to-background ratio (TBR) and maximum standardized uptake value (SUVmax), for recurrence and metastasis. The study of 11 patients revealed that 68Ga-FAPI-46 was more effective than other tracers for detecting metastases, with 55 vs. 49 metastases in the lymph nodes, 4 vs. 3 in the liver, and 4 vs. 3 in the bones detected in comparison to 18F-FDG. No significant differences were observed in 68Ga-DOTATATE and 68Ga-Pentixafor PET images. In addition, in five patients, the SUVmax and TBR values in 68Ga-FAPI-46 PET images were significantly higher than those in 18F-FDG PET images for lymph nodes and bone metastases. Although the SUVmax in 68Ga-FAPI-46 and 18F-FDG PET images for liver metastases was comparable, 68Ga-FAPI- 46 had a significantly higher TBR than 18F-FDG. Our findings suggest that FAPI PET/CT is not suitable for evaluating GBM and Ewing sarcoma but generally outperforms 18F-FDG PET/CT in various types of breast cancer, gastrointestinal, gynecological, PTC and MTC. However, larger trials are needed to validate these preliminary findings.

Increased imaging ligand hydrophilicity and improved pharmacokinetic properties provides enhanced in vivo targeting of fibroblast activation protein

In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing cell line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance (t1/2 = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance (t1/2 = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.

Aspergillus fumigatus: Is Dual-Tracer 18FDG/68Ga-FAPI PET/CT Capable of Distinguishing Fungal Infection and Unspecific Inflammation From Recurrent Lung Cancer?

A 61-year-old woman, referred for recurrent pneumonia over a period of 3 months with insufficient response to antibiotic treatment, presented with coughing and intense right-sided chest pain. Previously, she underwent right upper lobectomy for locally advanced non-small cell lung cancer (squamous cell carcinoma) followed by adjuvant chemotherapy and subsequent partial chest wall resection with polytetrafluoroethylene net insert due to a pleurocutaneous fistula. 18FDG plus a 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT scans were performed to rule out non-small cell lung cancer recurrence. Pathological workup with bronchoscopy and endobronchial ultrasound-guided transbronchial fine-needle aspiration of the lymph nodes showed no evidence of malignancy, but microbiology confirmed Aspergillus fumigatus infection of the middle lobe. Thus, the patient transitioned from antibiotic to antifungal therapy; no second-line oncologic treatment was initiated.

Development and Evaluation of DOTA-FAPI-Maleimide as a Novel Radiotracer for Tumor Theranostic with Extended Circulation.

This study aimed to evaluate a novel albumin-binding strategy for addressing the challenge of insufficient tumor retention of fibroblast activation protein inhibitors (FAPIs). Maleimide, a molecule capable of covalent binding to free thiol groups, was modified to conjugate with FAPI-04 in order to enhance its binding to endogenous albumin, resulting in an extended blood circulation half-life and increased tumor uptake. DOTA-FAPI-maleimide was prepared and radiolabeled with Ga-68 and Lu-177, followed by cellular assays, pharmacokinetic analysis, PET/CT, and SPECT/CT imaging to assess the probe distribution in various tumor-bearing models. Radiolabeling of the modified probe was successfully achieved with a radiochemical yield of over 99% and remained stable for 144 h. Cellular assays showed that the ligand concentration required for 50% inhibition of the probe was 1.20 ± 0.31 nM, and the Kd was 0.70 ± 0.07 nM with a Bmax of 7.94 ± 0.16 fmol/cell, indicative of higher specificity and affinity of DOTA-FAPI-maleimide compared to other FAPI-04 variants. In addition, DOTA-FAPI-maleimide exhibited a persistent blood clearance half-life of 7.11 ± 0.34 h. PET/CT images showed a tumor uptake of 2.20 ± 0.44%ID/g at 0.5 h p.i., with a tumor/muscle ratio of 5.64 in HT-1080-FAP tumor-bearing models. SPECT/CT images demonstrated long-lasting tumor retention. At 24 h p.i., the tumor uptake of [177Lu]Lu-DOTA-FAPI-maleimide reached 5.04 ± 1.67%ID/g, with stable tumor retention of 3.40 ± 1.95%ID/g after 4 days p.i. In conclusion, we developed and evaluated the thiol group-attaching strategy, which significantly extended the circulation and tumor retention of the adapted FAPI tracer. We envision its potential application for clinical cancer theranostics.

FAPI-PET-CT for quantification of the tissue response in rheumatic diseases

Fibroblast activation protein (FAP) is mainly found on the surface of activated fibroblasts but is not expressed on the surface of inactive fibroblasts. Selective FAP inhibitors (FAPI), which are coupled to a radioactive tracer, can be used to quantify profibrotic and proinflammatory fibroblasts in patients using FAPI positron emission tomography (PET) computed tomography (CT). Following initial applications in neoplastic diseases, FAPI-PET/CT is also increasingly being applied in rheumatological diseases. The first studies have shown that in patients with systemic sclerosis (SSc) FAPI accumulates in actively fibrotically remodeled pulmonary and myocardial areas, that a high FAPI accumulation is associated with the risk of short-term progression and that this accumulation in the lungs regresses after successful treatment. In cases of immunoglobulin 4 (IgG4)-associated diseases (IgG4 rheumatic disease, RD), the FAPI signal correlates with the histological accumulation of activated fibroblasts and a poorer response to treatment to inhibit inflammation. Fibroblasts in chronically inflamed tissue, such as patients with inflammatory joint diseases, vasculitis or myositis, also express FAP and can be quantified by FAPI-PET/CT. The treatment-induced change of the phenotype from a destructive IL-6+/MMP3+THY1+ fibroblast subtype to an inflammation inhibiting CD200+DKK3+ subtype can be mechanistically demonstrated using FAPI-PET/CT. These studies provide indications that FAPI-PET/CT enables quantification of the tissue response in patients with fibrosing and chronic inflammatory diseases and can be used for patient stratification; however, further studies are essential for validation of the use of FAPI-PET/CT as a molecular imaging marker.

Recent Clinical Implications of FAPI: Imaging and Therapy.

The fibroblast activation protein (FAP) is a biomarker that is selectively overexpressed on cancer-associated fibroblasts (CAFs) in various types of tumoral tissues and some nonmalignant diseases, including fibrosis, arthritis, cardiovascular, and metabolic diseases. FAP plays a critical role in tumor microenvironment through facilitating proliferation, invasion, angiogenesis, immunosuppression, and drug resistance. Recent studies reveal that FAP might be regarded as a promising target for cancer diagnosis and treatment. FAP-targeted imaging modalities, especially PET, have shown high sensitivity and specificity in detecting FAP-expressing tumors. FAP-targeted imaging can potentially enhance tumor detection, staging, and monitoring of treatment response, and facilitate the development of personalized treatment strategies. This study provides a comprehensive view of FAP and its function in the pathophysiology of cancer and nonmalignant diseases. It also will discuss the characteristics of radiolabeled FAP inhibitors, particularly those based on small molecules, their recent clinical implications in imaging and therapy, and the associated clinical challenges with them. In addition, we present the results of imaging and biodistribution radiotracer 68Ga-FAPI-46 in patients with nonmalignant diseases, including interstitial lung disease, primary biliary cirrhosis, and myocardial infarction, who were referred to our department. Our results show that cardiac FAP-targeted imaging can provide a novel potential biomarker for managing left ventricle remodeling. Moreover, this study has been organized and presented in a manner that offers a comprehensive overview of the current status and prospects of FAPI inhibitors in the diagnosis and treatment of diseases.

68Ga]Ga-labeled FAPI Conjugated with Gly-Pro Sequence for PET Imaging of Malignant Tumors.

To improve tumor uptake and prolong tumor retention, a novel fibroblast activation protein (FAP) ligand based on a quinoline-based FAP inhibitor (FAPI) conjugated with the Gly-Pro sequence and 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) was radiolabeled with [68Ga]GaCl3 ([68Ga]Ga-DOTA-GPFAPI-04). Due to the tumor heterogeneity, this study aimed to further validate the preclinical value of [68Ga]Ga-DOTA-GPFAPI-04 PET imaging in tumor mice models with different FAP expression levels. [68Ga]Ga-DOTA-GPFAPI-04 was synthesized and its partition coefficient was measured. The stability of [68Ga]Ga-DOTA-GPFAPI-04 was tested in phosphate-buffered saline (PBS, pH 7.4) and fetal bovine serum (FBS). Small animal PET and semi-quantitative studies were conducted in Panc-1 and A549 xenograft tumor mice models compared with [68Ga]Ga-DOTA-FAPI-04. Immunofluorescent and immunohistochemical staining and western blot assay were performed to confirm FAP expression in xenograft tumors. [68Ga]Ga-DOTA-GPFAPI-04 exhibited a radiochemical purity of > 99% and high stability in PBS and FBS. [68Ga]Ga-DOTA-GPFAPI-04 had higher hydrophilic property than [68Ga]Ga-DOTA-FAPI-04 (-4.09 ± 0.05 vs -3.45 ± 0.05). Small animal PET and semi-quantitative analysis revealed Panc-1 xenograft tumor displayed higher tumor uptake of [68Ga]Ga-DOTA-GPFAPI-04 and tumor-to-background ratios compared to A549 xenograft tumor, consistent with the results of immunofluorescence, immunohistochemistry, and western blot. Moreover, [68Ga]Ga-DOTA-GPFAPI-04 demonstrated higher tumor accumulation and longer tumor retention than [68Ga]Ga-DOTA-FAPI-04 in both Panc-1 and A549 xenograft tumors. Furthermore, the FAP-binding specificity of [68Ga]Ga-DOTA-GPFAPI-04 was confirmed in vivo by co-injection of unlabeled GPFAPI-04. [68Ga]Ga-DOTA-GPFAPI-04 showed more favorable in vivo tumor imaging and longer tumor retention compared to [68Ga]Ga-DOTA-FAPI-04, which has high potential to be a promising PET probe for detecting FAP-positive tumors.

Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used and has demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice.

Fibroblast Activation Protein-Directed Imaging Outperforms 18F-FDG PET/CT in Malignant Mesothelioma: A Prospective, Single-Center, Observational Trial.

The fibroblast activation protein (FAP) is highly expressed in tumor and stromal cells of mesothelioma and thus is an interesting imaging and therapeutic target. Previous data on PET imaging with radiolabeled FAP inhibitors (FAPIs) suggest high potential for superior tumor detection. Here, we report the data of a large malignant pleural mesothelioma cohort within a 68Ga-FAPI46 PET observational trial (NCT04571086). Methods: Of 43 eligible patients with suspected or proven malignant mesothelioma, 41 could be included in the data analysis of the 68Ga-FAPI46 PET observational trial. All patients underwent 68Ga-FAPI46 PET/CT, contrast-enhanced CT, and 18F-FDG PET/CT. The primary study endpoint was the association of 68Ga-FAPI46 PET uptake intensity and histopathologic FAP expression. Furthermore, secondary endpoints were detection rate and sensitivity, specificity, and positive and negative predictive values as compared with 18F-FDG PET/CT. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI46 SUVmax or SUVpeak and histopathologic FAP expression was significant (SUVmax: r = 0.49, P = 0.037; SUVpeak: r = 0.51, P = 0.030).68Ga-FAPI46 and 18F-FDG showed similar sensitivity by histopathologic validation on a per-patient (100.0% vs. 97.3%) and per region (98.0% vs. 95.9%) basis. Per-region analysis revealed higher 68Ga-FAPI46 than 18F-FDG specificity (81.1% vs. 36.8%) and positive predictive value (87.5% vs. 66.2%). Conclusion: We confirm an association of 68Ga-FAPI46 uptake and histopathologic FAP expression in mesothelioma patients. Additionally, we report high sensitivity and superior specificity and positive predictive value for 68Ga-FAPI46 versus 18F-FDG.

Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold.

Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.

99mTc-HFAPi SPECT imaging predicts left ventricular remodeling after acute myocardial infarction

BackgroundDespite improved treatments for acute myocardial infarction (AMI), myocardial fibrosis remains a key driver of adverse left ventricular (LV) remodeling and increased mortality. Fibroblast activation and proliferation significantly contribute to this process by enhancing cardiac fibrosis, which can lead to detrimental changes in LV structure. This study evaluates the effectiveness of 99mTc-labeled fibroblast activation protein inhibitor (99mTc-HFAPi) SPECT imaging in predicting LV remodeling over 12 months in post-AMI patients. MethodsA cohort of 58 AMI patients (46 males, median age 61 [53, 67] years) underwent baseline 99mTc-HFAPi imaging (5 ± 2 days post-MI), perfusion imaging (6 ± 2 days post-MI), and echocardiography (2 ± 2 days post-MI). Additionally, 15 patients had follow-up 99mTc-HFAPi and perfusion imaging, while 30 patients had follow-up echocardiography. Myocardial 99mTc-HFAPi activity was assessed at the patient level. LV remodeling was defined as a ≥10% increase in LV end-diastolic diameter (LVEDD) or LV end-systolic diameter (LVESD) from baseline to follow-up echocardiography. ResultsAMI patients displayed localized but non-uniform 99mTc-HFAPi uptake, exceeding perfusion defects. Baseline 99mTc-HFAPi activity exhibited significant correlations with BNPmax, LDHmax, cTNImax, and WBCmax, inversely correlating with LVEF. After 12 months, 11 patients (36.66%) experienced LV remodeling. Univariate regression analysis demonstrated an association between baseline 99mTc-HFAPi uptake extent and LV remodeling (OR = 2.14, 95%CI, 1.04, 4.39, P = 0.038). Conclusions99mTc-HFAPi SPECT imaging holds promise in predicting LV remodeling post-MI, providing valuable insights for patient management and prognosis.

Diagnostic Performances of PET/CT Using Fibroblast Activation Protein Inhibitors in Patients with Primary and Metastatic Liver Tumors: A Comprehensive Literature Review.

PET/CT using radiolabeled fibroblast activation protein inhibitors (FAPIs) is a promising diagnostic tool in oncology, especially when non-increased and/or physiologically high [18F]FDG uptake (as in liver parenchyma) is observed. We aimed to review the role of PET/CT using radiolabeled FAPIs in primary and/or metastatic liver lesions, and to compare their performances with more "conventional" radiopharmaceuticals. A search algorithm based on the terms "FAPI" AND ("hepatic" OR "liver") was applied, with the last update on 1st January 2024. Out of 177 articles retrieved, 76 studies reporting on the diagnostic application of radiolabeled FAPI PET/CT in at least one patient harboring primary or metastatic liver lesion(s) were fully analyzed. Although there was some heterogeneity in clinical conditions and/or study methodology, PET/CT with radiolabeled FAPIs showed an excellent performance in common primary liver malignancies (hepatocarcinoma, intrahepatic cholangiocarcinoma) and liver metastases (mostly from the gastrointestinal tract and lungs). A higher tumor-to-background ratio for FAPIs than for [18F]FDG was found in primary and metastatic liver lesions, due to lower background activity. Despite limited clinical evidence, radiolabeled FAPIs may be used to assess the suitability and effectiveness of FAPI-derived therapeutic agents such as [177Lu]Lu-FAPI. However, future prospective research on a wider population is needed to confirm the excellent performance.

Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the 68Ga- and 177Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2.

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. 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. 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. Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.

Covalent FAPI PET enables accurate management of medullary thyroid carcinoma: A prospective single-arm comparative clinical trial.

LBA6018 Background: Localizing medullary thyroid carcinoma (MTC) lesions is crucial for treatment decision, but the detection using the current imaging modalities is unsatisfied. Previously, we reported a 68Ga-labeled targeted covalent radiopharmaceutical fibroblast activation protein inhibitor (68Ga-TCR-FAPI), which demonstrated improved and sustained tumor targeting. This study aimed to head-to-head compare the 68Ga-TCR-FAPI PET-CT and the currently approved 18F-FDG PET-CT in detecting MTC. Methods: This was a prospective, single-center, open-labeled, single-arm comparative imaging trial. MTC patients with serum calcitonin>10 pg/ml and without targeted therapy were eligible. Serum calcitonin level, 68Ga-TCR-FAPI PET-CT and 18F-FDG PET-CT were acquired within a maximum interval of 30 days. Images were independently interpreted by 3 readers to calculate the patient-based and region-based detection rate. Quantitative PET parameters were calculated from the lesion ROI and compared between 68Ga-TCR-FAPI and 18F-FDG PET-CT. The accuracy of imaging findings was validated on lesions with histopathology or calcitonin-based follow-up. The primary outcome was patient-based detection rate, and the secondary outcome included region-based detection rates, metabolic parameters comparison and diagnostic accuracy. Results: 50 patients were enrolled between May 11th, 2023 and Feb. 1st, 2024. 68Ga-TCR-FAPI exhibited significantly higher patient-based detection rate than 18F-FDG PET-CT (98% vs. 66%, p=0.0002). Detection rates were also superior for 68Ga-TCR-FAPI in head and neck (72% vs. 50%, p=0.0098), thorax (50% vs. 34%, p=0.0269), abdomen (28% vs. 10%, p=0.0077) and skeleton (54% vs. 16%, p<0.0001). On quantitative analysis, SUVmax was significantly higher in 68Ga-TCR-FAPI PET-CT than 18F-FDG PET-CT (11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy was substantially greater with 68Ga-TCR-FAPI PET-CT than 18F-FDG PET-CT (96.7% vs. 43.3%, p<0.0001) based on 60 histopathological validated lesions from 15 patients who underwent surgery. Notably, 60% (30/50) patients directly benefited from 68Ga-TCR-FAPI PET-CT, with 66.7% (10/15) experiencing changes in surgical plans, and 100% (6/6) of the newly diagnosed MTC with R0 resection achieved biochemical cure at 1-month post-surgery. Conclusions: 68Ga-TCR-FAPI PET-CT displayed higher detection rate, metabolic value and diagnostic accuracy than 18F-FDG PET-CT in MTC patients, and should be integrated into MTC evaluation at initial diagnosis and persistent disease. Clinical trial information: NCT06084767 . [Table: see text]

Diagnostic accuracy and clinical value of [68Ga]Ga-FAPI-46 PET/CT for staging patients with ovarian cancer: study protocol for a prospective clinical trial

Background[18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) is recommended during diagnostic work-up for ovarian cancer; however, [18F]FDG PET has several inherent limitations. The novel oncologic PET-tracer fibroblast activation protein inhibitor (FAPI) has demonstrated promising results in multiple cancer types, including ovarian cancer, and could overcome the limitations of [18F]FDG PET; however, high-quality clinical studies are lacking. The primary objective of the present study is to compare the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT and [18F]FDG PET/CT in ovarian cancer patients and to investigate how this potential difference impacts staging and patient management.Methods and designFifty consecutive ovarian cancer patients will be recruited from Aalborg University Hospital, Denmark. This study will be a single-center, prospective, exploratory clinical trial that adheres to the standards for reporting diagnostic accuracy studies (STARD). This study will be conducted under continuous Good Clinical Practice monitoring. The eligibility criteria for patients are as follows: (1) biopsy verified newly diagnosed ovarian cancer or a high risk of ovarian cancer and referred for primary staging with [18F]FDG PET/CT; and (2) resectable disease, i.e., candidate for primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery. All recruited study subjects will undergo [68Ga]Ga-FAPI-46 PET/CT at primary staging, before primary debulking surgery or neoadjuvant chemotherapy (Group A + B), in addition to conventional imaging (including [18F]FDG PET/CT). Study subjects in Group B will undergo an additional [68Ga]Ga-FAPI-46 PET/CT following neoadjuvant chemotherapy prior to interval debulking surgery. The results of the study-related [68Ga]Ga-FAPI-46 PET/CTs will be blinded, and treatment allocation will be based on common clinical practice in accordance with current guidelines. The histopathology of surgical specimens will serve as a reference standard. A recruitment period of 2 years is estimated; the trial is currently recruiting.DiscussionTo our knowledge, this trial represents the largest, most extensive, and most meticulous prospective FAPI PET study conducted in patients with ovarian cancer thus far. This study aims to obtain a reliable estimation of the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT, shed light on the clinical importance of [68Ga]Ga-FAPI-46 PET/CT, and examine the potential applicability of [68Ga]Ga-FAPI-46 PET/CT for evaluating chemotherapy response.Trial registrationclinicaltrials.gov: NCT05903807, 2nd June 2023; and euclinicaltrials.eu EU CT Number: 2023-505938-98-00, authorized 11th September 2023.

The diagnostic value of [18F]FAPI-42 PET/CT for pulmonary artery masses: comparison with [18F]FDG PET/CT.

To investigate the potential utility of [18F]fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) for evaluating pulmonary artery (PA) masses, and compare it with [18F]fluorodeoxyglucose (FDG) PET/CT. Participants with clinically suspected PA malignancy were prospectively enrolled and underwent dual-tracer PET/CT ([18F]FAPI-42 and [18F]FDG) imaging. Visual analysis and semi-quantitative parameters were compared between the two types of radiotracers. The tissue specimen underwent immunohistochemical staining to verify FAP expression in the tissue. Thirty-three patients (18 males/15 females; mean age 53.1 ± 15.4 years) were enrolled. All 21 patients with malignant PA masses were FDG-positive (100%), whereas 20 out of 21 patients were FAPI-positive (95.2%). All 12 patients with benign PA masses were both negative in FDG and FAPI PET. The mean maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) of FAPI and FDG in malignant PA masses were significantly higher than those of benign masses. Although there was no significant difference in SUVmax between FDG and FAPI in malignant PA masses (11.36 vs. 9.18, p = 0.175), the TBR (liver) and TBR (left ventricle) were more favorable for FAPI than for FDG (13.04 vs. 5.17, p < 0.001); (median: 7.75 vs. 2.75, p = 0.007). Immunohistochemical analysis (n = 16) validated that the level of FAP expression corresponded strongly to the uptake of FAPI in PET/CT scans (rs = 0.712, p = 0.002). For clinical management, FAPI PET found more metastatic lesions than FDG PET in 4 patients, with 2 patients upgrading and 1 patient changing treatment decisions. FAPI PET/CT is feasible in the diagnosis of PA masses. Although not superior to FDG PET/CT, FAPI PET/CT showed better target-to-background contrast. This study found that FAPI PET/CT is not superior to FDG PET/CT in diagnosing PA masses, but FAPI PET/CT displays better target-to-background contrast and more positive lesions, which may help improve disease management. Pulmonary malignancies lack specificity in clinical manifestations, laboratory tests, and routine imaging examinations. FAPI PET/CT is not diagnostically better than FDG PET/CT but displays better target-to-background contrast and more positive lesions. Dual-tracer PET/CT ([18F]FAPI-42 and [18F]FDG) imaging improves clinical management of pulmonary artery masses.

[18F]FAPI adds value to [18F]FDG PET/CT for diagnosing lymph node metastases in stage I-IIIA non-small cell lung cancer: a prospective study

BackgroundThis study investigates the value of fluorine 18 ([18F])-labeled fibroblast activation protein inhibitor (FAPI) for lymph node (LN) metastases in patients with stage I-IIIA non-small cell lung cancer (NSCLC).MethodsFrom November 2021 to October 2022, 53 patients with stage I-IIIA NSCLC who underwent radical resection were prospectively included. [18F]-fluorodeoxyglucose (FDG) and [18F]FAPI examinations were performed within one week. LN staging was validated using surgical and pathological findings. [18F]FDG and [18F]FAPI uptake was compared using the Wilcoxon signed-ranks test. Furthermore, the diagnostic value of nodal groups was investigated.ResultsIn 53 patients (median age, 64 years, range: 31–76 years), the specificity of [18F]FAPI for detecting LN metastasis was significantly higher than that of [18F]FDG (P < 0.001). High LN risk category, greater LN short-axis dimension(≥ 1.0 cm), absence of LN calcification or high-attenuation, and higher LN FDG SUVmax (≥ 10.1) were risk factors for LN metastasis(P < 0.05). The concurrence of these four risk factors accurately predicted LN metastases (Positive Predictive Value [PPV] 100%), whereas the presence of one to three risk factors was unable to accurately discriminate the nature of LNs (PPV 21.7%). Adding [18F]FAPI in this circumstance improved the diagnostic value. LNs with an [18F]FAPI SUVmax<6.2 were diagnosed as benign (Negative Predictive Value 93.8%), and LNs with an [18F]FAPI SUVmax≥6.2 without calcification or high-attenuation were diagnosed as LN metastasis (PPV 87.5%). Ultimately, the integration of [18F]FDG and [18F]FAPI PET/CT resulted in the highest accuracy for N stage (83.0%) and clinical decision revisions for 29 patients.ConclusionIn patients with stage I-IIIA NSCLC, [18F]FAPI contributed additional valuable information to reduce LN diagnostic uncertainties after [18F]FDG PET/CT. Integrating [18F]FDG and [18F]FAPI PET/CT resulted in more precise clinical decisions.Trial registrationThe Chinese Clinical Trial Registry: ChiCTR2100044944 (Registered: 1 April 2021, https://www.chictr.org.cn/showprojEN.html?proj=123995).

Identifying intra-abdominal desmoid type fibromatosis mimicking recurrence/metastasis of GISTs using FAPI PET/CT.

e23516 Background: Intra-abdominal desmoid tumor (IADT) can mimic the recurrence/metastases of gastrointestinal stromal tumors (GISTs). However, it is difficult to radiologically differentiate IADT and recurrence/metastases of GISTs. This study aims to investigate the value of 18F fibroblast activation protein inhibitor ( [18F]FAPI-42) PET/CT in identifying intra-abdominal desmoid type fibromatosis mimicking recurrence/metastases of GISTs by comparing it to [18F]FDG PET/CT. Methods: This study retrospectively included a total of 24 patients (12 patients with IADT and 12 patients with recurrent/metastatic GISTs). The differences in [18F]FAPI-42 PET/CT parameters (SUVmax-FAPI and SUVTLR-FAPI ), [18F]FDG PET/CT parameters (SUVmax-FDG and SUVTLR-FDG), SUVfapi/SUVfdg ratio of IADT and GISTs were compared. The difference in PET/CT parameters (SUVmax, SUVTLR) of IADT between FDG PET/CT and FAPI PET/CT were compared. Immunohistochemical verification was performed on IADT lesions of all 12 patients and expression profiles of GEO datasets were analyzed to validate the FAP expression of IADT. Results: Both [18F]FAPI-42 PET/CT parameters, SUVmax-FAPI [8.8 (2.0, 16.0) vs 1.9 (1.0, 6.0), P&lt; 0.001]and SUVTLR-FAPI [7.3 (2.0, 15.8) vs 1.7 (0.5, 6.9), P&lt; 0.001], of IADT was significantly higher than that of GISTs, while there was no statistically significant difference in [18F]FDG PET/CT parameters, SUVmax-FDG and SUVTLR-FDG, between this two group. The ratio (SUVfapi/SUVfdg) of IADT was significantly higher than that of GISTs [3.3 (1.5, 8.0) vs 0.5 (0.1, 3.9), P= 0.001]. The SUVmax and SUVTLR of FAPI PET/CT of IADT were significantly higher than that of FDG PET/CT [8.8 (2.0, 16.0) vs 2.5 (1.1, 6.2), P&lt; 0.001; 7.3 (2.0, 15.8) vs 0.9 (0.4, 2.7), P&lt; 0.001; respectively]. FAP expression was found to be expressed in all the examined tissues and highly expressed in most of them. GEO database analysis shows that the FAP gene expression in DT is significantly higher than that in GISTs. Conclusions: FAPI PET/CT is a promising method in differentiating IADT from recurrence/metastases of GISTs compared with FDG PET/CT since FAP expression in DT is significantly higher than that in GISTs.

The Role of Fibroblast Activation Protein Inhibitor Positron Emission Tomography in Inflammatory and Infectious Diseases: An Updated Systematic Review.

The role of fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) is emerging for the assessment of non-oncological diseases, such as inflammatory and infectious diseases, even if the evidence in the literature is still in its initial phases. We conducted a systematic search of Scopus, PubMed/MEDLINE, Embase, and Cochrane library databases for studies published before 31 December 2023 reporting infectious and inflammatory disease imaging with FAPI PET/CT. We included twenty-one studies for a total of 1046 patients. The most frequent disease studied was lung interstitial disease, investigated in six studies for a total of 200 patients, followed by bone and joint diseases in two studies and 185 patients, IgG4-related disease in 53 patients, and Crohn's disease in 30 patients. Despite the heterogeneity of studies in terms of study design and technical features, FAPI PET/CT showed a high detection rate and diagnostic role. Moreover, when compared with 2-[18F]FDG PET/CT (n = 7 studies), FAPI PET/CT seems to have better diagnostic performances. The presence of chronic inflammation and tissue remodeling, typical of immune-mediated inflammatory conditions, may be the underlying mechanism of FAPI uptake.