Fibroblast Activation Protein Inhibitor Research Articles

Fibroblast activation protein inhibitor PET/CT as an emerging diagnostic modality in interstitial lung disease and other fibrotic conditions.

Interstitial lung diseases (ILD) encompass a wide range of disorders characterized by alveolar inflammation and fibrotic tissue remodeling, marked by significant morbidity and mortality. Systemic sclerosis (SSc), among other connective tissue diseases, is a frequent cause of ILD. Assessment of pulmonary fibrosis is frequently constrained by the delayed manifestations of profibrotic activation of fibroblasts, which results in late macroscopic alterations detectable by standard imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) scans. 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI [fibroblast activation protein inhibitor]) are novel radionuclides used in the selective positron emission tomography/computed tomography (PET/CT) detection of profibrotic fibroblasts, a key player in fibrotic tissue remodeling. Application of 68Ga-FAPI in different target organs undergoing fibrosis, such as lung and heart, highlights its efficacy in detecting ongoing fibrotic processes, since FAPI tracer uptake has been correlated with clinical disease progression markers in SSc-ILD. This feature could enable physicians to detect subclinical fibrotic activity and tailor an individualised therapy plan on a case by case basis. The use of 68Ga-FAPI in ILD and other fibrotic conditions may emerge as a novel tool in future clinical practice for both activity monitoring and treatment optimisation. Other tracers tested in ILD of different etiologies have shown promising results and may in future also be considered for potential application in SSc-ILD.

Negative 18F-FDG and Positive 68Ga-FAPI-04 Findings in a Patient With Acute Exacerbation of Chronic Cholecystitis.

Acute cholecystitis typically exhibits intense FDG uptake of the gallbladder wall. Radiolabeled fibroblast activation protein inhibitor (FAPI) is considered as a potential alternative agent for tumor-specific imaging. We report 18F-FDG and 68Ga-FAPI-04 PET/MR findings in a 44-year-old woman with acute exacerbation of chronic cholecystitis. The lesions show negative 18F-FDG uptake but intense 68Ga-FAPI-04 uptake in PET/MR. This case highlights the imperative for nuclear medicine clinicians to exercise vigilance when evaluating gallbladder lesions exhibiting intense 68Ga-FAPI-04 but negative 18F-FDG uptake.

Physiological Gallbladder Accumulation on 68 Ga-FAPI-46 PET/CT.

Radiolabeled fibroblast activation protein inhibitors (FAPIs) are a novel approach in cancer detection and treatment. Targeting fibroblast activation protein, extensively produced by cancer-associated fibroblasts, FAPI plays a key role in tumor development. Its advanced imaging capabilities offer clearer results in solid tumors compared with traditional methods, drawing significant interest in oncology. Additionally, FAPI's activity in conditions requiring tissue remodeling, such as atherosclerosis and arthritis, highlights its broader potential. This interesting image shows the physiological accumulation of 68 Ga-FAPI in the gallbladder, emphasizing the importance of accurate interpretation to prevent misdiagnoses and ensure effective patient management.

Sensitive quantification of fibroblast activation protein and high-throughput screening for inhibition by FDA-approved compounds

Fibroblast activation protein (FAP) has been extensively studied as a cancer biomarker for decades. Recently, small-molecule FAP inhibitors have been widely adopted as a targeting moiety of experimental theranostic radiotracers. Here we present a fast qPCR-based analytical method allowing FAP inhibition screening in a high-throughput regime. To identify clinically relevant compounds that might interfere with FAP-targeted approaches, we focused on a library of FDA-approved drugs. Using the DNA-linked Inhibitor Antibody Assay (DIANA), we tested a library of 2667 compounds within just a few hours and identified numerous FDA-approved drugs as novel FAP inhibitors. Among these, prodrugs of cephalosporin antibiotics and reverse transcriptase inhibitors, along with one elastase inhibitor, were the most potent FAP inhibitors in our dataset. In addition, by employing FAP DIANA in the quantification mode, we were able to determine FAP concentrations in human plasma samples. Together, our work expands the repertoire of FAP inhibitors, analyzes the potential interference of co-administered drugs with FAP-targeting strategies, and presents a sensitive and low-consumption ELISA alternative for FAP quantification with a detection limit of 50 pg/ml.

Valvular and Myocardial Fibroblast Activation in Aortic Stenosis

Activated fibroblasts drive leaflet thickening and left ventricular decompensation in aortic stenosis. Gallium-68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) binds to these key effector cells, and provides a readout of fibroblast activation. We aimed to describe the role of activated fibroblasts in patients with aortic stenosis in vivo using 68Ga-FAPI. In a prospective observational study, patients with aortic stenosis and control subjects underwent echocardiography, 68Ga-FAPI PET, CT, and MRI. Valvular and myocardial 68Ga-FAPI uptake was quantified using maximal standardised uptake values (SUVmax), and target-to-background ratio (TBRmax). Aortic stenosis severity was measured by peak velocity on echocardiography and the CT calcium score. Myocardial fibrosis was quantified by late gadolinium enhancement (LGE) on MRI. 86 patients with aortic valve disease (72±11 years, 68% male) plus 9 matched control subjects (72±9 years, 67%% male) participated. Increased 68Ga-FAPI uptake was observed in the aortic valves of patients with aortic stenosis compared with controls (p<0.001). 68Ga-FAPI TBRmax correlated with peak velocity (r=0.532, p<0.0010) and calcium score (r = 0.577, p<0.001). 54 patients (69%) had myocardial 68Ga-FAPI uptake, of whom 30 (38%) also had LGE corresponding to the region of 68Ga-FAPI uptake. Myocardial 68Ga-FAPI uptake correlated with increased indexed left ventricular mass (r=0.429, p<0.001) and indexed Extracellular Volume (r=0.404, p<0.001). For the first time, we have described valvular and myocardial fibroblast activation in patients with aortic stenosis in vivo. Valvular fibroblast activation is increased in patients with aortic stenosis, correlating with increased disease severity. Myocardial fibroblast activation is seen in the majority of patients with aortic stenosis in areas with and without established fibrosis, and is associated with adverse left ventricular remodelling. 68Ga-FAPI PET can visualise the key effector cell driving aortic valve disease, and may have a role in monitoring disease modifying treatments, as well as identifying patients at high risk of myocardial decompensation. Please click on the 'PDF' for the full abstract!

Correlation of FAPI PET Uptake with Immunohistochemistry in Explanted Lungs from Patients with Advanced Interstitial Lung Disease.

Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of 68Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis (n = 2), rheumatoid arthritis-associated ILD (n = 1), and nonspecific interstitial pneumonia (n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUVmax and SUVmean showed a positive correlation with the immunohistochemical FAP expression score (SUVmax: r = 0.57, P = 0.001; SUVmean: r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD.

Variable Tracer Avidity and Interlesional Heterogeneity on 18 F-FDG, 68 Ga-DOTATATE, and 68 Ga-DOTA-FAPi-04 PET/CT Imaging in a Single Individual Patient With Progressive Metastatic Medullary Thyroid Carcinoma.

In medullary thyroid carcinoma (MTC), distant metastases have few therapeutic options with low success rates and substantial toxicity in many patients, warranting exploration of alternate systemic treatments with fewer adverse effects. The fibroblast activation protein inhibitor (FAPI)-based PET/CT opens new avenues for several cancers, including MTC. A case of MTC with varying tracer avidity and interlesional heterogeneity on 18 F-FDG, 68 Ga-DOTATATE, and 68 Ga-DOTA-FAPI-04 PET/CT imaging is presented. 68 Ga-DOTA-FAPI-04 PET/CT exhibited superior efficacy in terms of visualization of metastatic soft tissue, lymph nodal, and skeletal lesions, with enhanced target-to-background ratio compared with the other two, facilitating the detection of these lesions, thereby demonstrating the potential for theranostic translation.

Head to head comparison of 18F-FDG and Al18F-NOTA-FAPI-04 PET/CT imaging used in diagnosis of autoimmune rheumatic diseases.

The aim of this study was to determine the performance of radionuclide-labeled fibroblast activation protein inhibitors (Al18F-NOTA-FAPI-04) PET/CT in patients with autoimmune rheumatic diseases (ARDs) and compare it with fluorine-18 (18F) labeled fluorodeoxyglucose (FDG) imaging. Fifty-eight participants with ARDs were prospectively enrolled from April 2022 to February 2024 and underwent dual-tracer PET/CT imaging. For both 18F-FDG and Al18F-NOTA-FAPI-04 PET/CT, imaging findings were interpreted and compared. The clinical significance was compared between18F-FDG PET/CT and Al18F-NOTA-FAPI-04 PET/CT imaging. 18F-FDG imaging was positive in 53 out of 58 cases (91.4%) while Al18F-NOTA-FAPI-04 imaging was positive in 55 out of 58 cases (94.8%). Overall positive rate of Al18F-NOTA-FAPI-04 imaging was as high as 18F-FDG imaging (P = 0.625). 18F-FDG imaging detected more lesions in lymph node, spleen, and bone marrow. Al18F-NOTA-FAPI-04 imaging detected more lesions in the lung, muscle, and tendon/ligament. There was no statistical difference of composing ratio of grades of clinical significance between two imaging modalities (χ2 = 2.875, P = 0.238). The superior rate of Al18F-NOTA-FAPI-04 PET/CT imaging was higher than 18F-FDG imaging (P = 0.020). In subgroup of adult-onset Still's disease, 18F-FDG imaging showed better performance than Al18F-NOTA-FAPI-04 imaging. In most of the other subgroup of ARDs, Al18F-NOTA-FAPI-04 PET/CT imaging overperformed 18F-FDG imaging. Both 18F-FDG and Al18F-NOTA-FAPI-04 PET/CT imaging have excellent sensitivity in ARDs. The detection capabilities of two tracers varied according to the involving organs of ARDs. In most of ARDs except adult-onset Still's disease, Al18F-NOTA-FAPI-04 PET/CT imaging overperformed 18F-FDG imaging. Key Points • 18F-FDG and Al18F-NOTA-FAPI-04 PET/CT imaging have excellent sensitivity in diagnosing of ARDs. • 18F-FDG PET/CT imaging detected more lesions in lymph node, spleen, and bone marrow. • 18F-NOTA-FAPI-04 PET/CT imaging detected more lesions in the lung, muscle, and tendon/ligament. • 18F-NOTA-FAPI-04 PET/CT imaging overperformed18F-FDG in most subgroups of ARDs.

Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer with [68Ga]Ga-FAPI-04 PET, [18F]FDG PET, and Contrast-Enhanced MRI: Lesion-to-Lesion Comparison with Pathology.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. 68Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/MRI, [18F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter's sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [68Ga]Ga-FAPI-04 PET/MRI and [18F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [68Ga]Ga-FAPI-04 change in SULpeak percentage, where SULpeak is SUVpeak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [68Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SULpeak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

18F]AlF-NOTA-FAPI-04 PET/CT for Predicting Pathologic Response of Resectable Esophageal Squamous Cell Carcinoma to Neoadjuvant Camrelizumab and Chemotherapy: A Phase II Clinical Trial.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of 18F-labeled fibroblast activation protein inhibitor ([18F]AlF-NOTA-FAPI-04, denoted as 18F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent 18F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On 18F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUVmax (area under the curve [AUC], 0.87; P = 0.0026), SUVpeak (AUC, 0.89; P = 0.0017), SUVmean (AUC, 0.88; P = 0.0021), TBRmax (AUC, 0.86; P = 0.0031), and TBRmean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%-81.82% and specificities of 83.33%-100%. Changes in SUVmax (AUC, 0.81; P = 0.0116), SUVpeak (AUC, 0.82; P = 0.0097), SUVmean (AUC, 0.81; P = 0.0116), and TBRmean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: 18F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

Prospective Study Comparing [99mTc]Tc-DP-FAPI Quantitative SPECT/CT with [68Ga]Ga-FAPI-04 PET/CT in Patients with Gastrointestinal Tumors.

Over the past decade, [68Ga]Ga-FAPI-04 positron emission tomography (PET)/CT imaging has been widely used for the treatment of various tumors. However, the application of 99mTC-labeled fibroblast activation protein inhibitors in tumors has been less studied. Our team previously demonstrated the safe biological distribution of [99mTc]Tc-DP-FAPI in the human body. Based on this, this study reports the accuracy of [99mTc]Tc-DP-FAPI in the imaging diagnosis of gastrointestinal tumors and compares it with that of [68Ga]Ga-FAPI-04 to evaluate the differences. A total of 24 patients with clinically diagnosed gastrointestinal tumors were prospectively included. All patients received [99mTc]Tc-DP-FAPI quantitative SPECT/CT imaging on the first day and [68Ga]Ga-FAPI-04 PET/CT imaging on the second day. And the effectiveness of the two imaging probes in detecting suspicious lesions was analyzed and compared. The primary tumors of all 24 patients were well detected by two imaging probes, and the sensitivity of [99mTc]Tc-DP-FAPI and [68Ga]Ga-FAPI-04 to the primary lesions was 100%. [99mTc]Tc-DP-FAPI examined 21 lymph nodes with a sensitivity and specificity of 32.8% and 10.9%, and [68Ga]Ga-FAPI-04 detected 57 lymph nodes with a sensitivity and specificity of 89.1% and 67.2%, respectively. Three distant metastases were detected by [99mTc]Tc-DP-FAPI and nine metastases by [68Ga]Ga-FAPI-04. The study showed that [99mTc]Tc-DP-FAPI is highly sensitive to detecting primary lesions of gastrointestinal tumors. Compared with [68Ga]Ga-FAPI-04, [99mTc]Tc-DP-FAPI has the same sensitivity in detecting primary tumors but has certain limitations in detecting metastases. [99mTc]Tc-DP-FAPI is of great value for preliminary screening of tumor lesions and early diagnosis of disease in patients who are suspected of having gastrointestinal tumors.

Fibroblast activation protein inhibitor positron emission tomography imaging in muscles of patients with idiopathic inflammatory myopathy.

Mesenchymal stromal cells in muscles participate in regeneration following muscle injury. This study explored the potential of [18F]fibroblast activation protein inhibitor (FAPI)-42 positron emission tomography (PET) targeting mesenchymal stromal cells to evaluate disease activity of idiopathic inflammatory myopathy (IIM). Patients with IIM (n = 26) were prospectively included and underwent [18F]FAPI-42 PET/CT and whole-body MRI between January 2023 and July 2023. Patients with malignancies were retrospectively included in the control group and only underwent [18F]FAPI-42 PET/CT (n = 28). [18F]FAPI-42 PET/CT images were evaluated using for avid-FAPI uptake and the target-to-background ratio (TBR). Whole-body MRI was evaluated for oedema, fatty infiltration, and atrophy in 42 muscles in the IIM group. The global FAPI- and MRI-derived parameters were calculated for each. . Clinical assessment of disease activity and muscle strength were collected. Patients with IIM had significantly higher global FAPI-avid muscle ratios (0.68 [interquartile range (IQR): 0.45, 0.79] vs 0.06 [IQR: 0, 0.11], p< 0.001) and global muscle TBR (2.26 [IQR: 1.71, 2.75] vs 1.23 [IQR: 1.02, 1.52], p< 0.001) compared with controls. In the IIM group, the median TBR was higher in muscles with oedema than in those without (2.44 [IQR: 1.46, 3.27] vs 1.31 [IQR: 0.95, 1.99], p< 0.001). Global FAPI-avid muscle ratios significantly correlated with global oedema score (r = 0.833), muscle strength (r=-0.649), serum creatine kinase (r = 0.456), and disease activity index (r = 0.495-0.621). Increased [18F]FAPI-42 uptake was associated with muscle oedema in IIM. FAPI-derived parameters correlated with IIM disease activity. [18F]FAPI-42 is a promising PET tracer for evaluating IIM disease activity.

68Ga]Ga-DOTAGA-Glu(FAPi)2 Shows Enhanced Tumor Uptake and Theranostic Potential in Preclinical PET Imaging.

The use of fibroblast activation protein inhibitors (FAPis) for positron emission tomography (PET) imaging in cancer has garnered significant interest in recent years, yielding promising results in preclinical and clinical settings. FAP is predominantly expressed in pathological conditions such as fibrosis and cancer, making it a compelling target. An optimized approach involves using FAPi homodimers as PET tracers, which enhance tumor uptake and retention, making them more effective candidates for therapy. Here, a UAMC-1110 inhibitor-based homodimer, DOTAGA-Glu(FAPi)2, was synthesized and radiolabeled with gallium-68, and its efficacy was evaluated in vivo for PET imaging in an endogenously FAP-expressing xenografted mouse model, U87MG. Notably, 45 min post-injection, the mean uptake of [68Ga]Ga-DOTAGA-Glu(FAPi)2 was 4.7 ± 0.5% ID/g in the tumor with low off-target accumulation. The ex vivo analysis of the FAP expression in the tumors confirmed the in vivo results. These findings highlight and confirm the tracer's potential for diagnostic imaging of cancer and as a theranostic companion.

Personalised PET imaging in oncology: an umbrella review of meta-analyses to guide the appropriate radiopharmaceutical choice and indication.

For several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies. We performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [18F]FDG, somatostatin- receptor-targeting 68Ga-DOTA-peptides, 18F-labelled dihydroxyphenylalanine ([18F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours. The literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [18F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [68Ga]Ga- DOTA-TOC and -TATE) or [18F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers. The comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations.

Role of [18F]FAPI-04 in staging and therapeutic management of intrahepatic cholangiocarcinoma: prospective comparison with [18F]FDG PET/CT

BackgroundFluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has some limitations in diagnosis of Intrahepatic cholangiocarcinoma (ICC).Materials and methodsPatients with histologically confirmed ICC who underwent both [18F]FDG and 18F-labeled fibroblast-activation protein inhibitors ([18F]FAPI)-04 PET/CT were prospectively analyzed. The maximum standard uptake value (SUVmax), tumor-to-background ratio (TBR), metabolic tumor volume (MTV), total lesion glycolysis (TLG), [18F]FAPI–avid tumor volume (FTV), total lesion fibroblast activation protein expression (TLF) were compared between the two modalities by paired Wilcoxon signed-rank test and Mann–Whitney U test, and McNemar’s test was used to assess the diagnostic accuracy between the two techniques.ResultsIn total, 23 patients with 389 lesions were included. Compared to [18F]FDG, [18F]F-FAPI-04 PET/CT demonstrated a higher detection rate for intrahepatic lesions (86.3% vs. 78.2% P = 0.040), lymph node metastases (85.2% vs. 68.2%, P = 0.007), peritoneal metastases (100% vs. 93.8%), and bone metastases (100% vs. 70.5%, P < 0.001). [18F]FAPI-04 PET showed higher SUVmax, TBR and greater tumor burden values than [18F]FDG PET in non-cholangitis intrahepatic lesions (SUVmax: 8.7 vs. 6.4, P < 0.001; TBR: 8.0 vs. 3.5, P < 0.001; FTV vs. MTV: 41.3 vs. 12.4, P < 0.001; TLF vs. TLG: 223.5 vs. 57.0, P < 0.001), lymph node metastases (SUVmax: 6.5 vs. 5.5, P = 0.042; TBR: 5.4 vs. 3.9, P < 0.001; FTV vs. MTV: 2.0 vs. 1.5, P = 0.026; TLF vs. TLG: 9.0 vs. 7.8 P = 0.024), and bone metastases (SUVmax: 9.7 vs. 5.25, P < 0.001; TBR: 10.8 vs. 3.0, P < 0.001; TLF vs. TLG: 9.8 vs. 4.2, P < 0.001). However, [18F]FDG showed higher radiotracer uptake (SUVmax: 14.7 vs. 8.4, P < 0.001; TBR: 7.4 vs. 2.8, P < 0.001) than [18F]FAPI-04 PET/CT for 6 patients with obstructive cholangitis. [18F]FAPI-04 PET/CT yielded a change in planned therapy in 6 of 23 (26.1%) patients compared with [18F]FDG.Conclusions[18F]FAPI-04 PET/CT had higher detection rate and radiotracer uptake than [18F]FDG PET/CT in intrahepatic lesions, lymph node metastases, and distant metastases, especially in bone. Therefore, [18F]FAPI-04 PET/CT may be a promising technique for diagnosis and staging of ICC.Trial registrationClinical Trials, NCT05485792. Registered 1 August 2022, retrospectively registered, https//clinicaltrials.gov/study/NCT05485792?cond=NCT05485792&rank=1.

Evaluation of 68Ga-FAPI PET/CT and 18F-FDG PET/CT for the diagnosis of recurrent colorectal cancers

ObjectiveThe present study aimed to compare the diagnostic value of gallium-68-labeled fibroblast activation protein inhibitor positron emission tomography/computed tomography (68Ga-FAPI PET/CT) and fluorine-18-labeled fluorodeoxyglucose PET/CT (18F-FDG PET/CT) for detecting recurrent colorectal cancers (CRCs). Materials and MethodsFifty-six patients (age: 18–80 years, 31 men and 25 women) with suspected recurrent CRC were enrolled and underwent 18F-FDG PET/CT and 68Ga-FAPI PET/CT sequentially within 1 week. The maximum standard uptake value (SUVmax), tumor-to-background ratio (TBR), and diagnostic accuracy were estimated and compared between the two modalities by using Student’s t-test. The Wilcoxon signed-rank test was used to compare peritoneal carcinoma index (PCI) scores between the two imaging modalities. Results68Ga-FAPI PET/CT showed higher sensitivity for detecting recurrence (93 % vs. 79 %); lymph node metastasis (89 % vs. 78 %), particularly peritoneal lymph node metastasis (92 % vs. 63 %); and metastatic implantation on the intestinal wall (100 % vs. 25 %) compared to 18F-FDG PET/CT. However, 68Ga-FAPI PET/CT showed lower sensitivity for detecting bone metastasis (67 % vs. 100 %). The mean SUVmax values of peritoneal metastases and metastatic implantation on the intestinal wall were 4.28 ± 2.70 and 7.58 ± 1.66 for 18F-FDG PET/CT and 5.66 ± 1.97 and 6.70 ± 0.25 for 68Ga-FAPI PET/CT, respectively. Furthermore, 68Ga-FAPI PET/CT showed significantly higher TBR for peritoneal metastatic lesions (4.22 ± 1.47 vs. 1.41 ± 0.89, p < 0.0001) and metastatic implantation on the intestinal wall (5.63 ± 1.24 vs. 2.20 ± 0.5, p = 0.02) compared to 18F-FDG PET/CT. For the same patient, 68Ga-FAPI PET/CT yielded a more accurate PCI score and a greater area under the curve value for the receiver operating characteristic curve (p < 0.01) than 18F-FDG PET/CT. Conclusion68Ga-FAPI PET/CT was superior to 18F-FDG PET/CT for detecting recurrence and peritoneal metastases. Hence, we propose the combination of these two modalities for better clinical diagnosis and management of patients with CRC.

Is There a Role for FAPI PET in Urological Cancers?

This work aims to investigate the utility of positron emission tomography/computed tomography (PET/CT) with fibroblast activation protein inhibitors (FAPI) in urological neoplasms, including prostate cancer, urothelial carcinoma, and renal cell carcinoma. Although the available data are very preliminary, FAPI PET showed potential for detecting primary prostate cancer with low prostate-specific membrane antigen expression, while prostate-specific membrane antigen PET/CT outperformed FAPI PET/CT in detecting biochemical recurrence. In urothelial carcinoma, FAPI PET/CT demonstrated increased detection rates compared with deoxy-2-[18F]fluoro-D-glucose PET/CT, in particular in small lymph node metastases, whose identification is still an unmet clinical need. Limited data are available for renal cell carcinoma. In conclusion, FAPI PET emerges as a promising imaging modality for urological neoplasms, in particular bladder cancer. Further research is warranted to establish its role in guiding therapeutic decisions and as a potential novel theranostic agent.

Talabostat, fibroblast activation protein inhibitor, attenuates inflammation and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis, where activated fibroblasts play a pivotal role in disease progression. This study aimed to investigate the potential of Talabostat, a small molecule inhibitor of dipeptidyl peptidases, in alleviating fibrosis and inflammation associated with SSc pathogenesis. Dermal fibroblasts were obtained from skin biopsies of ten diffuse cutaneous SSc patients and healthy controls. These fibroblasts were subjected to treatment with either TGF-β alone or in combination with Talabostat. Immunofluorescence staining was conducted to evaluate FAPα and α-SMA protein levels. The expression of activated fibroblast markers (FAPα and ACAT2), pro-fibrotic (COL1A1 and COL1A2), anti-fibrotic (MMP1, MMP2, and MMP9), and inflammatory (IL-6 and TGFβ1) related genes was measured by quantitative real-time PCR. Talabostat-treated fibroblasts were assessed for their migratory capacity using a scratch assay and for their viability through MTT assay and Annexin V staining. The basal expression of COL1A1 and TGFβ1 was notably higher in healthy subjects, while MMP1 expression showed a significant increase in SSc patients. Furthermore, TGF-β stimulation led to upregulation of activated fibroblast markers, pro-fibrotic, and inflammatory-related genes in SSc-derived fibroblasts, which were attenuated upon Talabostat treatment. Interestingly, Talabostat treatment resulted in an upregulation of MMP9 expression. Moreover, Talabostat exhibited a concentration-dependent inhibition of activated fibroblast viability in both healthy and SSc fibroblasts, and suppressed fibroblast migration specifically in SSc patients. In summary, Talabostat modulates fibrotic genes in SSc, thereby inhibiting myofibroblast differentiation, activation, and migration. These findings suggest promising therapeutic avenues for targeting fibrosis in SSc.

Magnetic Resonance Imaging of Fibroblast Activation Protein Using a Targeted Gadolinium-Based Contrast Agent.

The aim of this study was to synthesize a quinoline-based MRI contrast agent, Gd-DOTA-FAPI04, and assess its capacity for targeting fibroblast activation protein (FAP)-positive tumors in vivo. Gd-DOTA-FAPI04 was synthesized by attaching a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complex of gadolinium(III) to FAP inhibitor FAPI04. The longitudinal relaxation time (T1) of the contrast agent was measured using a Siemens Prisma 3.0T MR system, and the CCK-8 assay was performed to evaluate its potential cytotoxicity. Male nude mice bearing tumors grown from FAP-expressing fibrosarcoma cells were divided into experimental (n = 4) and control (n = 4) groups, and T1-weighted image enhancement was measured at different times (0, 10, 30, 60, 90, and 120 min) postinjection of Gd-DOTA-FAPI04. The control group received an additional preinjection of excess FAPI04. FAP expression in tumor tissue was investigated by using immunohistochemistry with an anti-FAP antibody. The longitudinal relaxivities of gadodiamide and Gd-DOTA-FAPI04 were measured to be 3.734 mM-1 s-1 and 5.323 mM-1 s-1, respectively. The CCK-8 assay demonstrated that Gd-DOTA-FAPI04 has minimal toxicity to cultured human fibrosarcoma cells. In vivo MRI showed that peak accumulation of Gd-DOTA-FAPI04 in FAP-expressing tumors occurred 1 h postinjection and could be blocked by preinjection of excess FAPI04. Immunohistochemical analysis of harvested tumor tissue supported the above findings. Gd-DOTA-FAPI04 is a promising contrast agent for in vivo imaging of FAP.

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.