Fibroblast Activation Protein Inhibitor Research Articles

Rational Design and Comparison of Novel 99mTc-Labeled FAPI Dimers for Visualization of Multiple Tumor Types.

Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99mTc-labeled dimeric HF2 with high tumor uptake and image contrast. The dimeric HF2 was synthesized and radiolabeled with 99mTc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [99mTc]Tc-TPPTS-HF2, [99mTc]Tc-EDDA-HF2, and [99mTc]Tc-TPPMS-HF2 dimers. SPECT imaging results indicated that [99mTc]Tc-TPPTS-HF2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [99mTc]Tc-EDDA-HF2 and [99mTc]Tc-TPPMS-HF2. Notably, [99mTc]Tc-TPPTS-HF2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [99mTc]Tc-TPPTS-HF. Moreover, [99mTc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99mTc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [99mTc]Tc-TPPTS-HF2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.

Abstract PS05-01: Accuracy and safety of fibroblast activation protein inhibitor (FAPI) PET/CT in diagnosis of axillary lymph node metastasis in early breast cancer patients: a prospective cohort study (PFB-01&02 study)

Abstract Background Axillary lymph node (ALN) is the most common metastatic site of breast cancer (BC) and the status of ALN determines the staging, treatment and prognosis for BC patients. Traditional imaging techniques, including ultrasound (US), mammography, MRI, and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) were still unsatisfactory to evaluate the status of ALN non-invasively. Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts and FAP inhibitor (FAPI) PET has been found quite promising in BC. Well-designed prospective large cohort study concerning the diagnostic performance and safety profile of FAPI PET/CT in detection of ALN metastasis of BC is still lacking. Furthermore, FAPI could be radio-labeled with different radio-nuclides including 68Ga and 18F, and there is yet no data concerning the 18F-labeled FAPI in BC. In this study, we investigated the accuracy of FAPI (both 68Ga-FAPI-04 and Al18F-FAPI-04) PET/CT in newly diagnosed BC patients for assessing ALN metastasis. We also compared the diagnostic performance of FAPI PET/CT with that of 18F-FDG PET/CT and US. Methods This prospective study was approved by the Peking Union Medical College Hospital Ethics Committee and was registered online at NIH ClinicalTrials.gov (NCT05574907, NCT05574920). The inclusion criteria were as follows: (1) age 18-80 years old; (2) newly diagnosed BC confirmed by biopsy or with BI-RADS category 4C or 5 lesions by US. The exclusion criteria were as follows: (1) pregnancy or lactation; (2) patients unwilling to undergo PET/CT scans. All patients received biopsy or surgery on breast lesion and ALN. Patients received FAPI and 18F-FDG PET/CT after enrollment. The safety profile of FAPI PET was monitored after injection using the Common Terminology Criteria for Adverse Events. Two experienced nuclear medicine physicians, who were blinded to the pathological diagnosis and other imaging results, assessed the PET/CT images. It was defined as visually positive if the radioactive uptake of the ALN was higher than that of the adjacent normal tissue. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each diagnostic test. The McNemar test was applied to compare the differences of sensitivity and specificity between FAPI PET/CT, 18F-FDG PET/CT, and US. All statistical tests were performed two-sided, and P< 0.05 was considered statistically significant. Results In total, 113 patients (27-79 years old, median age 66) were enrolled. 53 patients underwent 68Ga-FAPI-04 PET/CT, and the other 60 patients underwent Al18F-FAPI-04 PET/CT. All patients underwent 18F-FDG PET/CT and US. A total of 53/113 (46.9%) patients were finally diagnosed with ALN metastasis. The sensitivity, specificity, accuracy, PPV, and NPV were 90.6%, 90.0%, 90.3%, 88.9%, and 91.5% for FAPI PET/CT, 84.9%, 73.3%, 78.8%, 73.8%, and 84.6% for 18F-FDG PET/CT, 83.0%, 76.7%, 79.6%, 75.9%, and 83.6% for US, respectively (Table 1). The specificity of FAPI PET/CT was significantly higher than that of 18F-FDG PET/CT (P < 0.05) and US (P < 0.05). The sensitivity of FAPI PET/CT was higher than that of 18F-FDG PET/CT (P= 0.45) and US (P= 0.29). There was no significant difference of sensitivity and specificity between 18F-FDG PET/CT and US (P > 0.05). The sensitivity, specificity, accuracy, PPV, and NPV were 92.0%, 92.9%, 92.5%, 92.0%, and 92.9% for 68Ga-FAPI-04 PET/CT, and 89.3%, 87.5%, 88.3%, 86.2%, and 90.3% for Al18F-FAPI-04 PET/CT, respectively (Table 2). The 68Ga-FAPI-04 PET/CT and Al18F-FAPI-04 PET/CT procedures were well tolerated in all patients. The only adverse event was injection pain in 12/53 (22.6%) patients injected with 68Ga-FAPI-04, and 7/69 (10.1%) patients injected with Al18F-FAPI-04, which might relate to the ethanol in the imaging agent. Conclusion The FAPI PET/CT outperformed 18F-FDG PET/CT and US in the diagnosis of ALN metastasis among early breast cancer patients. The 68Ga-FAPI-04 and Al18F-FAPI-04 PET/CT have similar diagnostic performance. The FAPI PET/CT procedures were well tolerated in all patients. Table 1 Diagnostic performance of FAPI PET/CT, 18F-FDG PET/CT, and ultrasound in the diagnosis of ALN metastasis Table 2 Diagnostic performance of 68Ga-FAPI-04 and Al18F-FAPI-04 PET/CT in diagnosis of ALN metastasis Citation Format: Bo Pan, Zhixin Hao, Chao Ren, Lifan Zhang, Yidong Zhou, Qiang Sun, Li Huo. Accuracy and safety of fibroblast activation protein inhibitor (FAPI) PET/CT in diagnosis of axillary lymph node metastasis in early breast cancer patients: a prospective cohort study (PFB-01&02 study) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-01.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Molecular Imaging of Fibroblast Activation in Rabbit Atherosclerotic Plaques: a Preclinical PET/CT Study.

Atherosclerosis remains the pathological basis of myocardial infarction and ischemic stroke. Early and accurate identification of plauqes is crucial to improve clinical outcomes of atherosclerosis patients. Our study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-04 PET/CT in identifying plaques via a preclinical rabbit model of atherosclerosis. New Zealand white rabbits were fed high-fat diet (HFD), and randomly divided into the model group injured by the balloon, and the sham group only with incisions. Ultrasound was performed to detect plaques, and FAPI-avid was determined through Al18F-NOTA-FAPI-04 PET/CT. Mean standardized uptake values (SUVmean) in lesions were compared, and biodistribution of Al18F-NOTA-FAPI-04 and target-to-background ratios (TBRs) were calculated. Histological staining was performed to display arterial plaques, and autoradiography (ARG) was employed to measure the in vitro intensity of Al18F-NOTA-FAPI-04. At last, the correlation among FAP levels, plaque area, SUVmean values and fibrous cap thickness was assessed. The rabbit carotid and abdominal atherosclerosis model was established. Al18F-NOTA-FAPI-04 showed a higher uptake in carotid plaques (SUVmean 1.32 ± 0.11) and abdominal plaques (SUVmean 0.73 ± 0.13) compared to corresponding controls (SUVmean 1.07 ± 0.06; 0.46 ± 0.03) (P < 0.05). Biodistribution analysis of Al18F-NOTA-FAPI-04 revealed that the bigger plaques were delineated with higher TBRs. Pathological staining showed the formation of arterial plaques, and ARG staining exhibited a higher intensity of Al18F-NOTA-FAPI-04 in the bigger plaques. Lastly, plaque area was found to be positively correlated to FAP expression and SUVmean, while FAP expression was negatively correlated to fibrous cap thickness of plaques. We successfully achieve molecular imaging of fibroblast activation in atherosclerotic lesions of rabbits, suggesting Al18F-NOTA-FAPI-04 PET/CT may be a potentially valuable tool to identify plaques.

A Systematic Review on the Diagnostic Value of Fibroblast Activation Protein Inhibitor PET/CT in Genitourinary Cancers.

In contemporary oncologic diagnostics, molecular imaging modalities are pivotal for precise local and metastatic staging. Recent studies identified fibroblast activation protein as a promising target for molecular imaging across various malignancies. Therefore, we aimed to systematically evaluate the current literature on the utility of fibroblast activation protein inhibitor (FAPI) PET/CT for staging patients with genitourinary malignancies. Methods: A systematic Embase and Medline search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) process, on August 1, 2023. Relevant publications reporting on the diagnostic value of FAPI PET/CT in genitourinary malignancies were identified and included. Studies were critically reviewed using a modified version of a tool for quality appraisal of case reports. Study results were summarized using a narrative approach. Results: We included 22 retrospective studies with a cumulative total of 69 patients, focusing on prostate cancer, urothelial carcinoma of the bladder and of the upper urinary tract, renal cell carcinoma, and testicular cancer. FAPI PET/CT was able to visualize both local and metastatic disease, including challenging cases such as prostate-specific membrane antigen (PSMA)-negative prostate cancer. Compared with radiolabeled 18F-FDG and PSMA PET/CT, FAPI PET/CT showed heterogeneous performance. In selected cases, FAPI PET/CT demonstrated superior tumor visualization (i.e., better tumor-to-background ratios and visualization of small tumors or metastatic deposits visible in no other way) over 18F-FDG PET/CT in detecting local or metastatic disease, whereas comparisons with PSMA PET/CT showed both superior and inferior performances. Challenges in FAPI PET/CT arise from physiologic urinary excretion of most FAPI radiotracers, hindering primary-lesion visualization in the bladder and upper urinary tract, despite generally providing high tumor-to-background ratios. Conclusion: The current findings suggest that FAPI PET/CT may hold promise as a future tool to aid clinicians in detecting genitourinary malignancies. Given the substantial heterogeneity among the included studies and the limited number of patients, caution in interpreting these findings is warranted. Subsequent prospective and comparative investigations are anticipated to delve more deeply into this innovative imaging modality and elucidate its role in clinical practice.

Fibroblast activation in sarcoidosis as assessed by 68Ga-FAPI (fibroblast activation protein inhibitor)-46 PET/CT.

Fibroblast activation in sarcoidosis as assessed by 68Ga-FAPI (fibroblast activation protein inhibitor)-46 PET/CT.

68Ga-DOTA-D-Alanine-BoroPro Radiotracer for Imaging of the Fibroblast Activation Protein in Malignant and Non-Malignant Diseases.

Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2',2″,2‴-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) as a novel radiotracer for PET imaging and evaluate its usefulness for FAP expression in malignant and non-malignant tissues. The coupling of p-SCN-benzene DOTA with HYNIC-iFAP was used for the chemical synthesis and further labeling with 68Ga. Radiochemical purity was verified by radio-HPLC. The specificity of 68Ga-iFAP was evaluated in HCT116 cells, in which FAP expression was verified by immunofluorescence and Western blot. Biodistribution and biokinetic studies were performed in murine models. 68Ga-iFAP uptake at the myocardial level was assessed in mice with induced infarction. First-in-human images of 68Ga-iFAP in healthy subjects and patients with myocardial infarction, glioblastoma, prostate cancer, and breast cancer were also obtained. DOTA-D-Alanine BoroPro was prepared with a chemical purity of 98% and was characterized by UPLC mass spectroscopy, FT-IR, and UV-vis. The 68Ga-iFAP was obtained with a radiochemical purity of >95%. In vitro and in vivo studies demonstrated 68Ga-iFAP-specific recognition for FAP, rapid renal elimination, and adequate visualization of the glioblastoma, breast tumor, prostate cancer, and myocardial infarction sites. The results of this research justify further dosimetry and clinical trials to establish the specificity and sensitivity of 68Ga-iFAP PET for FAP expression imaging.

Diagnostic Potential of Supplemental Static and Dynamic 68Ga-FAPI-46 PET for Primary 18F-FDG-Negative Pulmonary Lesions.

PET using 68Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68Ga-FAPI-46 PET in the 18F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68Ga-FAPI-46 PET in addition to 18F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUVmax, SUVmean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (68Ga-FAPI-46 in relation to18F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1, k 2, k 3, and k 4) were extracted from dynamic 68Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68Ga-FAPI-46 uptake, higher TBRs, and higher 68Ga-FAPI-46-to-18F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68Ga-FAPI-46-to-18F-FDG ratios regarding SUVmax and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.

Advances in the Development of Positron Emission Tomography Tracers for Improved Detection of Differentiated Thyroid Cancer.

Thyroid cancer poses a significant challenge in clinical management, necessitating precise diagnostic tools and treatment strategies for optimal patient outcomes. This review explores the evolving field of radiotracers in the diagnosis and management of thyroid cancer, focusing on prostate-specific membrane antigen (PSMA)-based radiotracers, fibroblast activation protein inhibitor (FAPI)-based radiotracers, Arg-Gly-Asp (RGD)-based radiotracers, and 18F-tetrafluoroborate (18F-TFB). PSMA-based radiotracers, initially developed for prostate cancer imaging, have shown promise in detecting thyroid cancer lesions; however, their detection rate is lower than 18F-FDG PET/CT. FAPI-based radiotracers, targeting fibroblast activation protein highly expressed in tumors, offer potential in the detection of lymph nodes and radioiodine-resistant metastases. RGD-based radiotracers, binding to integrin αvβ3 found on tumor cells and angiogenic blood vessels, demonstrate diagnostic accuracy in detecting radioiodine-resistant thyroid cancer metastases. 18F-TFB emerges as a promising PET tracer for imaging of lymph node metastases and recurrent DTC, offering advantages over traditional methods. Overall, these radiotracers show promise in enhancing diagnostic accuracy, patient stratification, and treatment selection in differentiated thyroid cancer, warranting further research and clinical validation. Given the promising staging capabilities of 18F-TFB and the efficacy of FAP-targeting tracers in advanced, potentially dedifferentiated cases, continued investigation in these domains is justified.

A rationally designed nuclei-targeting FAPI 04-based molecular probe with enhanced tumor uptake for PET/CT and fluorescence imaging.

Fibroblast activation protein inhibitor (FAPI) -based probes have been widely studied in the diagnosis of various malignant tumors with positron emission tomography/computed tomography (PET/CT). However, current imaging studies of FAPI-based probes face challenges in rapid clearance rate and potential false-negative results. Furthermore, FAPI has been rarely explored in optical imaging. Considering this, further modifications are imperative to improve the properties of FAPI-based probes to address existing limitations and broaden their application scenarios. In this study, we rationally introduced methylene blue (MB) to FAPIs, thereby imparting nuclei-targeting and fluorescence imaging capabilities to the probes. Furthermore, we evaluated the added value of FAPI-based fluorescence imaging to traditional PET/CT, exploring the potential application of FAPI-based probes in intraoperative fluorescence imaging. A new FAPI-based probe, namely NOTA-FAPI-MB, was designed for both PET/CT and fluorescence imaging by conjugation of MB. The targeting efficacy of the probe was evaluated on fibroblast activation protein (FAP)-transfected cell line and human primary cancer-associated fibroblasts (CAFs). Subsequently, PET/CT and fluorescence imaging were conducted on tumor-bearing mice. The tumor detection and boundary delineation were assessed by fluorescence imaging of tissues from hepatocellular carcinoma (HCC) patients. NOTA-FAPI-MB demonstrated exceptional targeting ability towards FAP-transfected cells and CAFs in comparison to NOTA-FAPI. This benefit arises from the cationic methylene blue (MB) affinity for anionic nucleic acids. PET/CT imaging of tumor-bearing mice revealed significantly higher tumor uptake of [18F]F-NOTA-FAPI-MB (standard uptake value of 2.20 ± 0.31) compared to [18F]F-FDG (standard uptake value of 1.66 ± 0.14). In vivo fluorescence imaging indicated prolonged retention at the tumor site, with retention lasting up to 24h. In addition, the fluorescent probes enabled more precise lesion detection and tumor margin delineation than clinically used indocyanine green (ICG), achieving a 100.0% (6/6) tumor-positive rate for NOTA-FAPI-MB while 33.3% (2/6) for ICG. These findings highlighted the potential of NOTA-FAPI-MB in guiding intraoperative surgical procedures. The NOTA-FAPI-MB was successfully synthesized, in which FAPI and MB simultaneously contributed to the targeting effect. Notably, the nuclear delivery mechanism of the probes improved intracellular retention time and targeting efficacy, broadening the imaging time window for fluorescence imaging. In vivo PET/CT demonstrated favorable performance of NOTA-FAPI-MB compared to [18F]F-FDG. This study highlights the significance of fluorescence imaging as an adjunct technique to PET/CT. Furthermore, the encouraging results obtained from the imaging of human HCC tissues hold promise for the potential application of NOTA-FAPI-MB in intraoperative fluorescent surgery guidance within clinical settings.

Early detection of anthracycline-induced cardiotoxicity using [68Ga]Ga-FAPI-04 imaging.

Anthracycline-induced cardiotoxicity (AIC), whose major manifestation is diffuse myocardial fibrosis, is an important clinical problem in cancer therapy. Therefore, early identification and treatment are clinically important. This study aims to explore the feasibility of using 68Ga-labelled fibroblast activation protein (FAP) inhibitor ([68Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) for the early identification of the fibrotic process and guidance of antifibrosis therapy in AIC. An AIC rat model was induced by the intravascular administration of doxorubicin (DOX) once per week for 1, 2, 3 and 6weeks (2.5mg/kg/injection, groups 1-4), whereas intravascular saline was administered to control rats. Experimental and control groups (n = 4) underwent [68Ga]Ga-FAPI PET/CT following disease induction. Groups 5 and 6 received DOX injections for 3 and 6weeks, treated with angiotensin-converting enzyme (ACE) inhibitor starting at 3weeks, treated with enalapril (20mg/kg, gastric gavage) daily and underwent echocardiography and [68Ga]Ga-FAPI PET/CT at 3weeks after treatment. Rat hearts were subjected to haematoxylin and eosin staining, FAP immunohistochemistry, Sirius red staining and Masson's trichrome staining to investigate the pathological changes and deposition of collagen fibres. Rat blood was sampled weekly for the enzyme-linked immunosorbent assay of various markers of myocardial injury, such as plasma cardiac troponin I, B-type natriuretic peptide and angiotensin II. [68Ga]Ga-FAPI-04 uptake by the heart was significantly higher in the cardiotoxicity group than in the control group at weeks 3 (SUVmax: 1.21 ± 0.23 vs 0.67 ± 0.01, P < 0.05) and 6 (SUVmax: 1.48 ± 0.28 vs 0.67 ± 0.08, P < 0.001), whereas left ventricle ejection fraction (LVEF) did not significantly differ between normal and AIC rats at week 3. FAP+ expression began to increase starting at week 3, before irreversible fibrotic changes were detected, until week 6. After 3weeks of enalapril treatment, [68Ga]Ga-FAPI-04 accumulation decreased in groups 5 and 6 (SUVmax decreased from 1.21 ± 0.23 to 0.77 ± 0.08 and 1.48 ± 0.28 to 1.09 ± 1.06, P < 0.05). Cardiac function was preserved (LVEF was 75.7% ± 7.38% in group 3 vs 74.5% ± 2.45% in group 5, P > 0.05) and improved (LVEF increased from 51.6% ± 9.03% in group 4 to 65.2% ± 4.27% in group 6, P < 0.05), and myocardial fibrosis attenuated (from 6.5% ± 1.2% in group 4 to 4.31% ± 0.37% in group 6, P < 0.01). [68Ga]Ga-FAPI PET/CT can be used for the early detection of active myocardial fibrosis in AIC and the evaluation of the efficacy of therapeutic interventions. Early treatment guided by [68Ga]Ga-FAPI PET/CT may reduce anthracycline-induced myocardial injury and improve heart function.

[18F] AlF-NOTA-FAPI-04 PET/CT for non-invasive assessment of tubular injury in kidney diseases

Abstract Background [18F] AlF-NOTA-FAPI-04 is a novel positron emission tomography (PET) ligand, which specifically targets fibroblast activation protein (FAP) expression as a FAP inhibitor (FAPI). We analyzed the diagnostic value of [18F] AlF-NOTA-FAPI-04 PET/CT for the non-invasive assessment of kidney interstitial inflammation and fibrosis in different renal pathologies. Methods Twenty-six patients (14 males and 12 females; mean age, 50.5 ± 16.5 years) with a wide range of kidney diseases and 10 patients (6 males and 4 females; mean age, 55.4 ± 8.6 years) without known evidence of renal disease as disease controls underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues obtained from kidney biopsies were stained with haematoxylin and eosin, periodic acid-Schiff, Masson's trichome, and periodic acid-silver methenamine. Immunohistochemical staining was also performed to assess the expression of α-smooth muscle actin (αSMA) and FAP. Renal parenchymal FAPI uptake reflected by maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) measurements on PET/CT was analyzed against pathohistological findings. Results We found that renal parenchymal FAPI uptake was significantly higher in patients with various kidney diseases than in control patients in this study (SUVmax = 4.3 ± 1.8 vs 1.9 ± 0.4, SUVmean=3.9 ± 1.7 vs 1.5 ± 0.4, respectively; all P &amp;lt; 0.001). All kidney diseases, both in acute and chronic kidney disease, had increased renal parenchymal uptake to varying degrees. The correlation analysis indicated a positive association between the SUVmax and the tubulointerstitial inflammation (TII), interstitial fibrosis and tubular atrophy (IF/TA), and TII + IF/TA scores (r = 0.612, 0.681, and 0.754, all P &amp;lt; 0.05), and between the SUVmean and the TII, IF/TA, and TII + IF/TA scores (r = 0.603, 0.700, and 0.748, all P &amp;lt; 0.05). Furthermore, we found significant positive correlations between both SUVmax and the SUVmean with SMA and FAP staining scores (r = 0.686 and 0.732, r = 0.667 and 0.739, respectively; both P &amp;lt; 0.001). Conclusions [18F] AlF-NOTA-FAPI-04 PET/CT is clinically available for the comprehensive and non-invasive assessment of tubular injury in various kidney diseases.

68Ga-FAPI-04 PET/CT in Non-Small Cell Lung Cancer: Accurate Evaluation of Lymph Node Metastasis and Correlation with Fibroblast Activation Protein Expression.

Fibroblast activation protein (FAP) is a promising diagnostic and therapeutic target in various solid tumors. This study aimed to assess the diagnostic efficiency of 68Ga-labeled FAP inhibitor (FAPI)-04 PET/CT for detecting lymph node metastasis in non-small cell lung cancer (NSCLC) and to investigate the correlation between tumor 68Ga-FAPI-04 uptake and FAP expression. Methods: We retrospectively enrolled 136 participants with suspected or biopsy-confirmed NSCLC who underwent 68Ga-FAPI-04 PET/CT for initial staging. The diagnostic performance of 68Ga-FAPI-04 for the detection of NSCLC was evaluated. The final histopathology or typical imaging features were used as the reference standard. The SUVmax and SUVmean, 68Ga-FAPI-avid tumor volume (FTV), and total lesion FAP expression (TLF) were measured and calculated. FAP immunostaining of tissue specimens was performed. The correlation between 68Ga-FAPI-04 uptake and FAP expression was assessed using the Spearman correlation coefficient. Results: Ninety-one participants (median age, 65 y [interquartile range, 58-70 y]; 69 men) with NSCLC were finally analyzed. In lesion-based analysis, the diagnostic sensitivity and positive predictive value of 68Ga-FAPI-04 PET/CT for detection of the primary tumor were 96.70% (88/91) and 100% (88/88), respectively. In station-based analysis, the diagnostic sensitivity, specificity, and accuracy for the detection of lymph node metastasis were 72.00% (18/25), 93.10% (108/116), and 89.36% (126/141), respectively. Tumor 68Ga-FAPI-04 uptake (SUVmax, SUVmean, FTV, and TLF) correlated positively with FAP expression (r = 0.470, 0.477, 0.582, and 0.608, respectively; all P ≤ 0.001). The volume parameters FTV and TLF correlated strongly with FAP expression in 31 surgical specimens (r = 0.700 and 0.770, respectively; both P < 0.001). Conclusion: 68Ga-FAPI-04 PET/CT had excellent diagnostic efficiency for detecting lymph node metastasis, and 68Ga-FAPI-04 uptake showed a close association with FAP expression in participants with NSCLC.

Preoperative evaluation of mediastinal lymph nodes in non-small cell lung cancer using [68Ga]FAPI-46 PET/CT: a prospective pilot study.

Mediastinal nodal staging is crucial for surgical candidate selection in non-small cell lung cancer (NSCLC), but conventional imaging has limitations often necessitating invasive staging. We investigated the additive clinical value of fibroblast activation protein inhibitor (FAPI) PET/CT, an imaging technique targeting fibroblast activation protein, for mediastinal nodal staging of NSCLC. In this prospective pilot study, we enrolled patients scheduled for surgical resection of NSCLC based on specific criteria designed to align with indications for invasive staging procedures. Patients were included when meeting at least one of the following: (1) presence of FDG-positive N2 lymph nodes, (2) clinical N1 stage, (3) central tumor location or tumor diameter of ≥ 3 cm, and (4) adenocarcinoma exhibiting high FDG uptake. [68Ga]FAPI-46 PET/CT was performed before surgery after a staging workup including [18F]FDG PET/CT. The diagnostic accuracy of [68Ga]FAPI-46 PET/CT for "N2" nodes was assessed through per-patient visual assessment and per-station quantitative analysis using histopathologic results as reference standards. Twenty-three patients with 75 nodal stations were analyzed. Histopathologic examination confirmed that nine patients (39.1%) were N2-positive. In per-patient assessment, [68Ga]FAPI-46 PET/CT successfully identified metastasis in eight patients (sensitivity 0.89 (0.52-1.00)), upstaging three patients compared to [18F]FDG PET/CT. [18F]FDG PET/CT detected FDG-avid nodes in six (42.8%) of 14 N2-negative patients. Among them, five were considered non-metastatic based on calcification and distribution pattern, and one was considered metastatic. In contrast, [68Ga]FAPI-46 PET/CT correctly identified all non-metastatic patients solely based on tracer avidity. In per-station analysis, [68Ga]FAPI-46 PET/CT discriminated metastasis more effectively compared to [18F]FDG PET/CT-based (AUC of ROC curve 0.96 (0.88-0.99) vs. 0.68 (0.56-0.78), P < 0.001). [68Ga]FAPI-46 PET/CT holds promise as an imaging tool for preoperative mediastinal nodal staging in NSCLC, with improved sensitivity and the potential to reduce false-positive results, optimizing the need for invasive staging procedures.

Nonmalignant 68 Ga-FAPI-46 Uptake in 2 Cases of TENIS Syndrome : Comparison With 18 F-FDG.

The cancer specificity of fibroblast activation protein inhibitor (FAPI) uptake remains understudied topic, and several cases of false-positive FAPI PET/CT findings have been reported. We present 2 patients of differentiated thyroid cancer with thyroglobulin elevation and negative iodine scintigraphy syndrome who underwent 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT for evaluation of any possible sites for metastatic disease. Although no focus of metastatic disease was found in these patients, remarkable findings were noticed instead. Nonmalignant FAPI uptake was evident in the gallbladder, uterus, and degenerative changes, whereas these uptake were discordant or partially concordant with those in FDG's, also CT images showed no underlying abnormality.

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma or a Metaphor for Heterogeneity: From Single-Cell Analysis to Whole-Body Imaging.

Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC, characterized by intense stromal desmoplastic reactions and a dominant presence of cancer-associated fibroblasts (CAFs), significantly contributes to therapeutic resistance. However, within the heterogeneous CAF population, fibroblast activation protein (FAP) emerges as a promising target for Gallium-68 FAP inhibitor positron emission tomography (Ga68FAPI-PET) imaging. Notably, 68Ga-FAPI-PET demonstrates promising diagnostic sensitivity and specificity, especially in conjunction with low tracer uptake in non-tumoral tissues. Moreover, it provides valuable insights into tumor-stroma interactions, a critical aspect of PDAC tumorigenesis not adequately visualized through conventional methods. The clinical implications of this innovative imaging modality extend to its potential to reshape treatment strategies by offering a deeper understanding of the dynamic TME. However, while the potential of 68Ga-FAPI-PET is evident, ongoing correlative studies are essential to elucidate the full spectrum of CAF heterogeneity and to validate its impact on PDAC management. This article provides a comprehensive review of CAF heterogeneity in PDAC and explores the potential impact of 68Ga-FAPI-PET on disease management.

Applications of FAPI PET/CT in the diagnosis and treatment of breast and the most common gynecologic malignancies: a literature review.

The fibroblast activating protein (FAP) is expressed by some fibroblasts found in healthy tissues. However, FAP is overexpressed in more than 90% of epithelial tumors, including breast and gynecological tumors. As a result, the FAP ligand could be used as a target for diagnosis and treatment purposes. Positron emission tomography/computed tomography (PET/CT) is a hybrid imaging technique commonly used to locate and assess the tumor's molecular and metabolic functions. PET imaging involves the injection of a radiotracer that tends to accumulate more in metabolically active lesions such as cancer. Several radiotracers have been developed to target FAP in PET/CT imaging, such as the fibroblast-activation protein inhibitor (FAPI). These tracers bind to FAP with high specificity and affinity, allowing for the non-invasive detection and quantification of FAP expression in tumors. In this review, we discussed the applications of FAPI PET/CT in the diagnosis and treatment of breast and the most common gynecologic malignancies. Radiolabeled FAPI can improve the detection, staging, and assessment of treatment response in breast and the most common gynecologic malignancies, but the problem with normal hormone-responsive organs remains insurmountable. Compared to the diagnostic applications of FAPI, further research is needed for future therapeutic applications.

Application Value of 68 Ga-FAPI PET/CT in the Evaluation of Myelofibrotic Diseases.

Fibroblast activation protein is highly expressed in neoplastic lesions and various fibrotic tissues, making it an attractive target for disease evaluation. 68 Ga-labeled fibroblast activation protein inhibitor (FAPI), a new tumor interstitial imaging agent, holds promise for evaluating myelofibrosis. Therefore, this study aimed to use 68 Ga-FAPI PET/CT for the noninvasive visualization and quantification of the extent of myelofibrosis. This was a prospective clinical study involving 22 patients with myelofibrosis who underwent 68 Ga-FAPI PET/CT. The uptake of 68 Ga-FAPI was measured in their respective bone marrow and spleen, and the obtained imaging findings were compared with laboratory, cytogenetic, and histopathological data. 68 Ga-FAPI uptake in the bone marrow was significantly and positively correlated with the myelofibrosis grade ( r > 0.8, P < 0.001). 68 Ga-FAPI PET/CT showed visually negative results in patients with grades 0-1 myelofibrosis and positive in those with grades 2-3, but the level of involvement varied. 68 Ga-FAPI PET/CT provides a noninvasive means of visualizing the extent of systemic bone marrow involvement and differentiation between the early and advanced stages of fibrosis. 68 Ga-FAPI PET/CT shows promise as a method for visualizing and quantifying myelofibrosis, providing suitable sites for bone marrow biopsy. The extent of 68 Ga-FAPI uptake by bone marrow increases with the progression of myelofibrosis, thus it is a simple and noninvasive measurement that can be used to evaluate the progression of myelofibrosis. Nevertheless, although 68 Ga-FAPI PET/CT has demonstrated a potential value in prognostic assessment, further confirmation is needed.

Properties of [18F]FAPI monitoring of acute radiation pneumonia versus [18F]FDG in mouse models

ObjectiveIn this study, the uptake characteristics of [18F]fibroblast activation protein inhibitor (FAPI) molecular imaging probe were investigated in acute radiation pneumonia and lung cancer xenografted mice before and after radiation to assess the future applicability of [18F]FAPI positron emission tomography/computed tomography (PET/CT) imaging in early radiotherapy response.MethodsInitially, the biodistribution of [18F]FAPI tracer in vivo were studied in healthy mice at each time-point. A comparison of [18F]FAPI and [18F]fluorodeoxyglucose (FDG) PET/CT imaging efficacy in normal ICR, LLC tumor-bearing mice was evaluated. A radiation pneumonia model was then investigated using a gamma counter, small animal PET/CT, and autoradiography. The uptake properties of [18F]FAPI in lung cancer and acute radiation pneumonia were investigated using autoradiography and PET/CT imaging in mice.ResultsThe tumor area was visible in [18F]FAPI imaging and the tracer was swiftly eliminated from normal tissues and organs. There was a significant increase of [18F]FDG absorption in lung tissue after radiotherapy compared to before radiotherapy, but no significant difference of [18F]FAPI uptake under the same condition. Furthermore, both the LLC tumor volume and the expression of FAP-ɑ decreased after thorax irradiation. Correspondingly, there was no notable [18F]FAPI uptake after irradiation, but there was an increase of [18F]FDG uptake in malignancies and lungs.ConclusionsThe background uptake of [18F]FAPI is negligible. Moreover, the uptake of [18F]FAPI may not be affected by acute radiation pneumonitis compared to [18F]FDG, which may be used to more accurately evaluate early radiotherapy response of lung cancer with acute radiation pneumonia.

[68Ga]Ga-FAP-2286, a novel promising theragnostic approach for PET/CT imaging in patients with various type of metastatic cancers.

Fibroblast activation protein (FAP) has emerged as a promising target for diagnosis and therapeutic intervention due to high expression and accumulation in the stromal compartments of a variety of malignant tumors. FAP-2286 utilizes cyclic peptides with FAP-binding characteristics to enhance the retention of the imaging agent within tumors, in contrast to the small-molecule FAP inhibitors (FAPI) like FAPI-04/46. The aim of this study was to quantify the tumor uptake of [68Ga] Gallium-FAP-2286 within primary solid tumors, adjacent excised tissues, and metastatic lesions. In this prospective study, 21 patients (average age 51.9) with various diagnoses of remaining and metastatic cancers participated. Among them, six had metastatic sarcoma, and 14 had adenocarcinoma, including eight breast, two rectum, two lung, two pancreas, and one thyroid cases. The patients underwent a [68Ga]Ga-FAP-2286 PET/CT scan. An hour post-administration of [68Ga]Ga-FAP-2286, a visual assessment of whole body scans and semi-quantification of the PET/CT results were carried out. The standardized uptake values (SUV)max of [68Ga]Ga-FAP-2286 in tumor lesions and the tumor-to-background ratio (TBR) were then calculated. The vital signs of the patients, such as heart rate, blood pressure, and temperature, were observed before, during, and after the diagnostic procedure during the 4-h follow-up. All individuals underwent the [68Ga]Ga-FAP-2286 PET/CT scans without any signs of drug-associated pharmacological effects. The PET/CT scans displayed substantial absorption of [68Ga]Ga-FAP-2286 in tumor lesions in all patients (100% (21/21)). Irrespective of the tumors' origins (epithelial or mesothelium) and whether they exhibited local recurrence, distant recurrence, or metastatic lesions, the PET/CT scans revealed the uptake of [68Ga]Ga-FAP-2286 in these lesions. Overall, these data suggest that [68Ga]Ga-FAP-2286 is a promising FAP derivative for efficient metastatic cancer diagnosis and being considered as a potential compound for therapeutic application in patients with advanced metastatic cancers.