Fibroblast Activation Protein Inhibitor Research Articles

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.

FAPi-Based Agents in Thyroid Cancer: A New Step towards Diagnosis and Therapy? A Systematic Review of the Literature.

(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to 131I, becoming more aggressive. In this scenario, [18F]FDG PET/CT imaging is used for evaluating the widespread nature of the disease, despite its low sensitivity and a false negative rate of 8-21.1%. A novel class of PET agents targeting the fibroblast activation protein inhibitor (FAPi) has emerged, studied particularly for their potential application to theranostics. (2) Methods: A search of the literature was performed by two independent authors (P.G. and L.E.) using the PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE databases. The following terms were used: "FAP" or "FAPi" or "Fibroblast activating protein" and "thyroid" or "thyroid cancer", in different combinations. The included papers were original articles, clinical studies, and case reports in the English language. No time limits were used. Editorials, conference papers, reviews, and preclinical studies were excluded. (3) Results: There were 31 papers that were selected. Some studies reported a low or absent FAPi uptake in TC lesions; others reported promising findings for the detection of metastases. (4) Conclusions: The preliminary results are encouraging. FAPI agents are an alternative to [18F]FDG and a promising theranostic tool. However, further studies with a larger population are needed.

Advances in Cancer Research: Current and Future Diagnostic and Therapeutic Strategies.

Cancers of unknown primary (CUP) exhibit significant cellular heterogeneity and malignancy, which poses significant challenges for diagnosis and treatment. Recent years have seen deeper insights into the imaging, pathology, and genetic characteristics of CUP, driven by interdisciplinary collaboration and the evolution of diagnostic and therapeutic strategies. However, due to their insidious onset, lack of evidence-based medicine, and limited clinical understanding, diagnosing and treating CUP remain a significant challenge. To inspire more creative and fantastic research, herein, we report and highlight recent advances in the diagnosis and therapeutic strategies of CUP. Specifically, we discuss advanced diagnostic technologies, including 12-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) or 68Ga-FAPI (fibroblast activation protein inhibitor) PET/CT, liquid biopsy, molecular diagnostics, self-assembling nanotechnology, and artificial intelligence (AI). In particular, the discussion will extend to the effective treatment techniques currently available, such as targeted therapies, immunotherapies, and bio-nanotechnology-based therapeutics. Finally, a novel perspective on the challenges and directions for future CUP diagnostic and therapeutic strategies is discussed.

Comparative analysis of [18F]F-FAPI PET/CT, [18F]F-FDG PET/CT and magnetization transfer MR imaging to detect intestinal fibrosis in Crohn's disease: A prospective animal model and human cohort study.

Accurately and early detection of intestinal fibrosis in Crohn's disease (CD) is crucial for clinical management yet remains an unmet need. Fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising tool to assess fibrosis. We aimed to investigate the diagnostic capability of [18F]F-FAPI PET/CT in detecting intestinal fibrosis and compared it with[18F]F-FDG PET/CT and magnetization transfer MR imaging (MTI). Twenty-two rats underwent TNBS treatment to simulate fibrosis development, followed by three quantitative imaging sessions within one week. Mean and maximum standardized uptake values (SUVmean and SUVmax) were calculated on[18F]F-FAPI and [18F]F-FDG PET/CT, along with normalized magnetization transfer ratio on MTI. Intestinal fibrosis was assessed pathologically, with MTI serving as imaging standard for fibrosis. The diagnostic efficacy of imaging parameters in fibrosis was compared using pathological and imaging standards. Ten patients with 34 bowel strictures were prospectively recruited to validate their diagnostic performance, using the identical imaging protocol. In CD patients, the accuracy of FAPI uptake (both AUCs = 0.87, both P ≤ 0.01) in distinguishing non-to-mild from moderate-to-severe fibrosis was higher than FDG uptake (both AUCs = 0.82, P ≤ 0.01) and comparable to MTI (AUCs = 0.90, P ≤ 0.001). In rats, FAPI uptake responded earlier to fibrosis development than FDG and MTI; consistently, during early phase, FAPI uptake showed a stronger correlation (SUVmean: R = 0.69) with pathological fibrosis than FDG (SUVmean: R = 0.17) and MTI (R = 0.52). The diagnostic efficacy of [18F]F-FAPI PET/CT in detecting CD fibrosis is superior to [18F]F-FDG PET/CT and comparable to MTI, exhibiting great potential for early detection of intestinal fibrosis.

Diagnostic and Therapeutic Application of Fibroblast Activation Protein Inhibitors in Oncologic and Nononcologic Diseases.

Fibroblast activation protein inhibitor positron emission tomography (PET) has gained interest for its ability to demonstrate uptake in a diverse range of tumors. Its molecular target, fibroblast activation protein, is expressed in cancer-associated fibroblasts, a major cell type in tumor microenvironment that surrounds various types of cancers. Although existing literature on FAPI PET is largely from single-center studies and case reports, initial findings show promise for some cancer types demonstrating improved imaging when compared with the widely used 18F-fludeoxyglucose PET for oncologic imaging. As we expand our knowledge of the utility of FAPI PET, accurate understanding of noncancerous uptake seen on FAPI PET is crucial for accurate evaluation. In this review, we summarize potential diagnostic and therapeutic applications of radiolabeled FAP inhibitors in oncological and nononcological disease processes.

Synthesis and Preliminary Study of 99mTc-Labeled HYNIC-FAPi for Imaging of Fibroblast Activation Proteins in Tumors.

Fibroblast activation protein (FAP) is an emerging target for cancer diagnosis. Different types of FAP inhibitor (FAPI)-based radiotracers have been developed and applied for tumor imaging. However, few FAPI tracers for single photon emission computed tomography (SPECT) imaging have been reported. SPECT imaging is less expensive and more widely distributed than positron emission tomography (PET), and thus, 99mTc-labeled FAPIs would be more available to patients in developing regions. Herein, we developed a FAPI-04-derived radiotracer, HYNIC-FAPi-04 (HFAPi), for SPECT imaging. 99mTc-HFAPi, with a radiochemical purity of >98%, was prepared using a kit formula within 30 min. The specificity of 99mTc-HFAPi for FAP was validated by a cell binding assay in vitro and SPECT/CT imaging in vivo. The binding affinity (Kd value) of 99mTc-HFAPi for human FAP and murine FAP was 4.49 and 2.07 nmol/L, respectively. SPECT/CT imaging in HT1080-hFAP tumor-bearing mice showed the specific FAP targeting ability of 99mTc-HFAPi in vivo. In U87MG tumor-bearing mice, 99mTc-HFAPi had a higher tumor uptake compared with that of HT1080-hFAP and 4T1-mFAP tumor models. Interestingly, 99mTc-HFAPi showed a relatively high uptake in some murine joints. 99mTc-HFAPi accumulated in tumor lesions with a high tumor-to-background ratio. A preliminary clinical study was also performed in breast cancer patients. Additionally, 99mTc-HFAPi exhibited an advantage over 18F-FDG in the detection of lymph node metastatic lesions in breast cancer patients, which is helpful in improving treatment strategies. In short, 99mTc-HFAPi showed excellent affinity and specificity for FAP and is a promising SPECT radiotracer for (re)staging and treatment planning of breast cancers.

FAPI PET/CT provides higher uptake and better target to back ground in recurrent and metastatic tumors of patients with Iodine refractory papillary thyroid cancer compared with FDG PET CT.

The role of fibroblast activation protein inhibitor (FAPI) PET CT scan is not well documented in papillary thyroid cancer (PTC) patients. Patients with radioiodine refractory PTC and high thyroglobulin levels need PET/CT scan which is generally done by 18F FDG. In the current study, the diagnostic performance of 68Ga FAPI and FDG PET/CT scans were compared head to head in patients with radioiodine refractory PTC. Fourteen patients with negative whole body Iodine scans and high thyroglobulin levels underwent whole body PET scans with, respectively, 120-310 and 145-370 MBq 68Ga FAPI-46 and 18F FDG. SUVmax of the back ground in the blood pool and liver and the hottest, largest and average neck, mediastinum, lung and bone lesions were calculated and compared. Ten patients had at least one active (SUVmax>blood pool) lesion similarly in two scans. The liver and blood pool SUVmax values were 1.25(0.2) and 1.7(0.2) in FAPI and 2.65(0.2) and 2.0(0.2) in FDG PET images, respectively. The difference was significant (p=0.001). Standard SUV of the hottest lesion to liver was above 3 in all FAPI scans but in half of FDG scans. Target lesion number and intensity were similar between two PET studies but in a patient out of 5 pulmonary metastatic patients, pulmonary nodules were negative (SUVmax=0.9) in FDG while positive (SUVmax= 3.8) in FAPI images (i.e. 20% patient upstaged). FAPI accumulates in the recurrent and metastatic lesions of patients with Iodine refractory PTC at least as well as FDG with particular privileges as lower injected activity and lower back ground.

Design, Preclinical Evaluation, and Clinical Translation of 68Ga-FAPI-LM3, a Heterobivalent Molecule for PET Imaging of Nasopharyngeal Carcinoma.

Extensive research has been conducted on radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2 (LM3) peptides for imaging of FAP and somatostatin receptor 2 (SSTR2)-positive tumors. In this study, we designed and synthesized a FAPI-LM3 heterobivalent molecule radiolabeled with 68Ga and evaluated its effectiveness in both tumor xenografts and patients with nasopharyngeal carcinoma (NPC). Methods: The synthesis of FAPI-LM3 was based on the structures of FAPI-46 and LM3. After radiolabeling with 68Ga, its dual-receptor-binding affinity was evaluated invitro and invivo. Preclinical studies, including small-animal PET and biodistribution evaluation, were conducted on HT-1080-FAP and HT-1080-SSTR2 tumor xenografts. The feasibility of 68Ga-FAPI-LM3 PET/CT in a clinical setting was evaluated in patients with NPC, and the results were compared with those of 18F-FDG. Results: 68Ga-FAPI-LM3 showed high affinity for both FAP and SSTR2. The tumor uptake of 68Ga-FAPI-LM3 was significantly higher than that of 68Ga-FAPI-46 and 68Ga-DOTA-LM3 in HT-1080-FAP-plus-HT-1080-SSTR2 tumor xenografts. In a clinical study involving 6 NPC patients, 68Ga-FAPI-LM3 PET/CT showed significantly higher uptake than did 18F-FDG in primary and metastatic lesions, leading to enhanced lesion detectability and tumor delineation. Conclusion: 68Ga-FAPI-LM3 exhibited FAPI and SSTR2 dual-receptor-targeting properties both invitro and invivo, resulting in improved tumor uptake and retention compared with that observed with monomeric 68Ga-FAPI and 68Ga-DOTA-LM3. This study highlights the clinical feasibility of 68Ga-FAPI-LM3 PET/CT for NPC imaging.

68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer.

BACKGROUNDImproving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-β receptor (TGF-βR) inhibitor that targets cancer-associated fibroblasts (CAFs) is promising for the enhancement of efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy.METHODSWe measured CAFs in vivo using the 68Ga-labeled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04) for PET/CT imaging to guide the combination of TGF-β inhibition and immunotherapy. One hundred thirty-one patients with metastatic colorectal cancer (CRC) underwent 68Ga-FAPI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging. The relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with the TGF-βR inhibitor combined with KN046, which blocks programmed death ligand 1 (PD-L1) and CTLA-4, followed by 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses.RESULTSPatients with metastatic CRC demonstrated high uptake rates of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. The TGF-βR inhibitor enhanced tumor-infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamic changes of CAFs and tumor response to combined the TGF-βR inhibitor with immunotherapy.CONCLUSION68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and the response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to guide precise TGF-β inhibition plus immunotherapy in CRC patients, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.TRIAL REGISTRATIONCFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry.FUNDINGNational Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).

18F-FAPI PET/CT performs better in evaluating mediastinal and hilar lymph nodes in patients with lung cancer: comparison with 18F-FDG PET/CT

BackgroundThe aim of this study was to evaluate the efficacy of fluorine 18 (18F) labeled fibroblast activation protein inhibitor (FAPI) in identifying mediastinal and hilar lymph node metastases and to develop a model to quantitatively and repeatedly identify lymph node status.MethodsTwenty-seven patients with 137 lymph nodes were identified by two PET/CT images. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of lymph node status were analyzed, and the optimal cut-off value was identified by ROC analysis.ResultsThe SUVmax of metastatic lymph nodes on 18F-FAPI was higher than that on 18F-FDG PET/CT (10.87 ± 7.29 vs 6.08 ± 5.37, p < 0.001). 18F-FAPI presented much greater lymph node detection sensitivity, specificity, accuracy, PPV and NPV than 18F-FDG PET/CT (84% vs. 71%; 92% vs. 67%; 90% vs. 69%, 84% vs. 52%, and 92% vs. 83%, respectively). Additionally, the diagnostic effectiveness of 18F-FAPI in small lymph nodes was greater than that of 18F-FDG PET/CT (specificity: 96% vs. 72%; accuracy: 93% vs. 73%; PPV: 77% vs. 33%, respectively). Notably, the optimal cut-off value for specificity and PPV of 18F-FAPI SUVmax was 5.3; the optimal cut-off value for sensitivity and NPV was 2.5.Conclusion18F-FAPI showed promising diagnostic efficacy in metastatic mediastinal and hilar lymph nodes from lung cancer patients, with a higher SUVmax, especially in small metastatic nodes, compared with 18F-FDG. In addition, this exploratory work recommended optimal SUVmax cutoff values to distinguish between nonmetastatic and metastatic lymph nodes, thereby advancing the development of image-guided radiation.Trial registration ClinicalTrials.gov identifier: ChiCTR2000036091.

A FAPI-conjugated FITC fluorescence probe for targeted cancer imaging

The targeted fluorescent probe, FITC-FAPI, can achieve high accumulation at the tumor site and extend the residence time of the fluorescent probe, resulting in clear tumor imaging.

Clinical applications of fibroblast activation protein‐targeted theranostics in oncologic and nononcologic disease: Current status and future directions

AbstractQuinoline‐based fibroblast activation protein (FAP) inhibitor (FAPI)‐based positron emission tomography (PET) imaging and radioligand therapy (RLT) are being investigated for use in a wide variety of diseases, and recent results have been promising. This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with 18F‐fluorodeoxyglucose. In addition, we summarize the previously published FAP‐targeted RLT data and discuss its current clinical use and future potential. Our qualitative summary can inform future research directions, medical guidelines, and optimal clinical decision‐making.

Diagnostic Accuracy of [68Ga]Ga Labeled Fibroblast-Activation Protein Inhibitors in Detecting Head and Neck Cancer Lesions Using Positron Emission Tomography: A Systematic Review and a Meta-Analysis.

Several studies have examined the use of positron emission tomography (PET) using [68Ga]Ga-radiolabeled fibroblast-activation protein inhibitors (FAPi) across multiple subtypes of head and neck cancer (HNC). The purpose of the present study was to evaluate the diagnostic accuracy of a newly developed molecular imaging approach in the context of HNC through a comprehensive review and meta-analysis. A thorough literature review was conducted to identify scholarly articles about the diagnostic effectiveness of FAP-targeted PET imaging. The present study incorporates original publications assessing the efficacy of this innovative molecular imaging test in both newly diagnosed and previously treated HNC patients. This systematic review examined eleven investigations, of which nine were deemed suitable for inclusion in the subsequent meta-analysis. The quantitative synthesis yielded a pooled detection rate of 99% for primary HNC lesions. Additionally, on a per patient-based analysis, the pooled sensitivity and specificity for regional lymph node metastases were found to be 90% and 84%, respectively. The analysis revealed a statistical heterogeneity among the studies for the detection rate of primary HNC lesions. The quantitative findings presented in this study indicate a favorable diagnostic performance of FAP-targeted PET imaging in detecting primary HNC tumors. In contrast, discordant results concerning the diagnostic accuracy of lymph node metastases were found. However, further multicentric trials are required to validate the efficacy of FAP-targeted PET in this specific group of patients.

Fibroblast Activation Protein–Targeted PET/CT With Al18F-NODA-FAPI-04 for In Vivo Imaging of Tendon Healing in Rat Achilles Tendon Injury Models

Background: Fibroblast activation protein (FAP) has shown high expression in inflammatory responses and fibrosis. Hypothesis: We speculated that FAP could serve as a diagnostic and monitoring target in the tendon healing process. Study Design: Controlled laboratory study. Methods: A total of 72 Sprague-Dawley rats were randomly divided into a tendon crush group and a half-partial tendon laceration group. Four rats in each group were injected with radiotracers weekly for 4 weeks after surgery, with aluminum fluoride–labeled 1,4,7-triazacyclononane-N,N′,N″-triacetic acid–conjugated FAP inhibitor (Al18F-NODA-FAPI-04) administered on the first day of each week and 18F-fludeoxyglucose (18F-FDG) on the next day. Small animal positron emission tomography (PET) imaging was performed, and tendon tissue was collected for pathology and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis each week after surgery. Results: One week after surgery, both radiotracers showed signal concentration at the lesion site, which was the highest radioactive uptake observed during 4 weeks postoperatively, consistent with the severity of the lesion. Consistent trends were observed for inflammatory cytokines during qRT-PCR analysis. Additionally, Al18F-NODA-FAPI-04 PET exhibited a more precise lesion pattern, attributed to its high specificity for naive fibroblasts when referring to histological findings. Over time, the uptake of both radiotracers at the injury site gradually decreased, with 18F-FDG experiencing a more rapid decrease than Al18F-NODA-FAPI-04. In the fourth week after surgery, the maximum standardized uptake values of Al18F-NODA-FAPI-04 in the injured lesion almost reverted to the baseline levels, indicating a substantial decrease in naive fibroblasts and inflammatory cells and a reduction in inflammation and fibrosis, especially compared with the first week. Corresponding trends were also revealed in pathological and qRT-PCR results. Conclusion: Our findings suggest that inflammation is a prominent feature during the early stage of tendon injury. Al18F-NODA-FAPI-04 PET allows accurate localization and provides detailed morphological imaging, enabling continuous monitoring of the healing progress and assessment of injury severity.

FAPI Uptake in Gallbladder Is It Normal Biodistribution?

Radiolabeled fibroblast activation protein inhibitors (FAPIs) have been extensively used in different types of cancers, although not yet FDA approved. Normal patterns of FAPI biodistribution have been investigated, and it is known that FAPI is expressed in nonmalignant pathophysiological lesions, characterized by tissue remodeling such as atherosclerosis, arthritis, and scar/fibrotic tissues. In this interesting image, we are presenting the accumulation of 68 Ga-FAPI in the gallbladder. This finding could be related to a normal distribution of the radiotracer as a physiologic finding. This is a potentially important finding as FAPI may be used as theragnostic agent in the future.

Synthesis and Evaluation of [18F]SiFA-Conjugated Ligands for Fibroblast Activation Protein Imaging.

In recent years, fibroblast activation protein (FAP) has emerged as an important target for the diagnosis and therapy of various tumors due to its high expression on the cell surface of cancer-associated fibroblasts, which are the major components of the tumor stroma. In this study, we synthesized and evaluated 18F-labeled FAP inhibitors (FAPIs) for FAP imaging. Two silicon fluoride acceptor (SiFA)-conjugated FAPIs were synthesized: one containing a γ-carboxy-l-glutamic acid (Gla) residue (1) and another containing two Gla residues (2). Both ligands exhibited high binding affinities for FAP. 18F/19F exchange reactions on both ligands were performed in the presence of 2% water. This resulted in the formation of radioligands [18F]1 and [18F]2 in high radiochemical yields. Radioligand [18F]2, with a more favorable partition coefficient, was selected for the U87MG cell binding study, and the results showed FAP-specific binding of the radioligand to the cells. An ex vivo biodistribution study in U87MG tumor-bearing mice 60 min after injection demonstrated a 5.8-fold higher tumor accumulation of [18F]2 than that of [18F]1. Furthermore, PET and ex vivo biodistribution studies of [18F]2 in U87MG tumor-bearing mice showed high and persistent tumor uptake over time, which was significantly blocked by the preinjection of FAPI-04. Our results indicate that [18F]SiFA-(Gla)2-conjugated FAPI ([18F]2) has the potential for FAP imaging.

Fibroblast activation protein-specific inhibitor imaging in heart failure

Abstract Background Although myocardial fibrosis can be quantified by magnetic resonance (MR), assessment of fibrosis activity is important as this will inform disease activity and the presence of ongoing adverse cardiac remodelling. Fibroblast activation protein (FAP) is expressed on the surface of activated myofibroblasts and is a marker of ongoing fibrosis activity. Radiolabelled FAP-specific ligands, such as 68-Gallium (68Ga)-FAP inhibitor (FAPI), represent a promising new approach to quantify fibrosis activity in the myocardium. Purpose To investigate whether 68Ga-FAPI positron emission tomography (PET)/MR can detect myocardial fibrosis activity in patients with heart failure with reduced ejection fraction. Methods In a prospective cross-sectional study, patients with heart failure with reduced ejection fraction and healthy volunteers underwent 68Ga-FAPI PET/MR. 10 patients had repeat imaging at 6 months. Standardised uptake values (SUVmax) and tissue to background ratios (TBR) were calculated within the left ventricular (LV) wall. Results Participants were predominantly middle-aged men: patients with heart failure (n=45; median age 65 [60-74] years, 76% male) and healthy volunteers (59 [56-62] years,70% male). LV ejection fraction was reduced in patients with heart failure (40±8%) but was normal in healthy volunteers (60±6%; P&amp;lt;0.001). Within the heart failure cohort, 22 patients had ischaemic cardiomyopathy and 23 patients had non-ischaemic cardiomyopathy. Compared with healthy volunteers, patients with heart failure had higher myocardial uptake of 68Ga-FAPI (SUVmax 3.2±1.5 versus 1.5±0.3, p&amp;lt;0.001; TBR 1.9±0.8 versus 1.1±0.2, p&amp;lt;0.001; Figure 1). Myocardial 68Ga-FAPI uptake was higher in patients with either ischaemic or non-ischaemic cardiomyopathy compared to healthy volunteers (SUVmax 4.0±1.7 and 2.3±0.5 versus 1.5±0.3 respectively; p&amp;lt;0.001 for both) and was higher in patients with ischaemic compared to non-ischaemic cardiomyopathy (p&amp;lt;0.001). Differential patterns of 68Ga-FAPI uptake were also observed with increased LV uptake seen particularly in the basal septum of patients with non-ischaemic cardiomyopathy and in the infarct zone of patients with ischaemic cardiomyopathy (Figure 2). Based on the Youden’s index of the receiver-operator curves, the optimal threshold for identifying myocardial fibrosis in patients with heart failure was SUVmax of 1.9 with a specificity of 90%, sensitivity of 89% and area under the curve of 0.94. At 6 months, 68Ga-FAPI uptake was unchanged in the 10 patients with chronic heart failure that underwent repeat scanning (p=0.91). Conclusion Increased myocardial fibrosis activity can be detected with 68Ga-FAPI PET/MR in patients with heart failure. Differential patterns of 68Ga-FAPI uptake are seen in patients with non-ischaemic cardiomyopathy or ischaemic cardiomyopathy. This may help characterise and prognosticate patients with heart failure and inform the future development of novel heart failure therapies.Figure 1Figure 2