Search Results (36)

Fibroblast activation protein (FAP) is a serine protease selectively expressed in cancer-associated fibroblasts (CAFs), fibrotic tissues, and areas of active tissue remodeling, making it an attractive target for diagnostic imaging across a spectrum of disease. FAP inhibitors (FAPIs) labeled with PET tracers have rapidly advanced as a novel imaging modality with broad clinical applications that offers several advantages, including rapid tumor accumulation, low background uptake, and high tumor-to-background ratios. In oncology, FAPI PET has demonstrated excellent performance in visualizing a wide range of malignancies, including those with low glycolytic activity, such as pancreatic cancer, cholangiocarcinoma, and certain sarcomas. Its high sensitivity and specificity for the stromal component enables improved tumor delineation, staging, and response assessment. Additionally, the potential to guide theranostic approaches, where the same tracer can be labeled with therapeutic radionuclides, positions FAPI as a key player in precision oncology. Beyond oncology, FAPI PET has shown promise in imaging conditions characterized by fibrotic and inflammatory processes. In the cardiovascular field, FAPI PET imaging is being investigated for its ability to detect myocardial fibrosis and active cardiac remodeling, crucial in conditions like heart failure, post-myocardial infarction remodeling, and hypertrophic cardiomyopathy. This review highlights the expanding clinical applications of FAPI-based PET imaging across oncology, inflammation, and cardiovascular disease. While the current data are promising, further large-scale studies and multicenter trials are essential to validate these findings and establish standardized protocols. The versatility and broad applicability of FAPI PET underscore its potential as a transformative tool in precision medicine. Full article

Background: This systematic review was performed to investigate the potential diagnostic role of fibroblast activation protein (FAP)-targeted radiopharmaceuticals in hepatocarcinoma (HCC) and cholangiocarcinoma (CCA). Methods: Relevant studies published between 2019 and 2023 were selected by searching PubMed and Scopus. The following data were extracted: authors, radiopharmaceuticals, sample size, country and year of publication, study design, and main results. Selected studies were analyzed using a modified version of the Critical Appraisal Skills Programme (CASP). Results: A total of 15 papers were finally selected, where 5 (33%) were retrospective, and 10 (67%) were prospective, with an overall number of 331 involved patients. Most of the studies (14/15, 93%) employed the FAP inhibitor series (FAPI), while only one research study used cyclic peptides as FAP-binding motifs. Twelve papers (80%) compared these FAP-targeted radiopharmaceuticals with ¹⁸F-FDG. The other 3/15 (20%) were not comparative studies and used exclusively ⁶⁸Ga-FAPI-04. ⁶⁸Ga-FAPI-04 is the most used radiopharmaceutical in analyzed studies (11/15, 73%), while other tracers, including ¹⁸F-FAPI, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAP-2286, were used in the remaining ones. Conclusions: FAP-targeted radiopharmaceuticals have good diagnostic accuracy in HCC and CCA, with potential and promising theragnostic applications. Full article

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

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

Triple-negative breast cancer (TNBC) presents limited therapeutic options and is associated with poor prognosis. Early detection and the development of novel therapeutic agents are therefore imperative. Fibroblast activation protein (FAP) is a membrane protein expressed on cancer-associated fibroblasts (CAFs) that plays an essential role in TNBC proliferation, migration, and invasion. Consequently, it is hypothesized that the Astatine (²¹¹At)-labeled FAP inhibitor (FAPI) selectively exerts anti-tumor effects through alpha-particle emission. In this study, we aimed to assess its theranostic capabilities by integrating [¹⁸F]FAPI-74 PET imaging with targeted alpha therapy using [²¹¹At]FAPI1 in TNBC models. Mice xenografts were established by transplanting MDA-MB-231 and HT1080 cells (control). As a parallel diagnostic method, [¹⁸F]FAPI-74 was administered for PET imaging to validate FAP expression. A single dose of [²¹¹At]FAPI1 (1.04 ± 0.10 MBq) was administered to evaluate the therapeutic efficacy. [¹⁸F]FAPI-74 exhibited high accumulation in MDA-MB-231 xenografts, and FAP expression was pathologically confirmed via immunostaining. The group that received [²¹¹At]FAPI1 (n = 11) demonstrated a significantly enhanced anti-tumor effect compared with the control group (n = 7) (p = 0.002). In conclusion, [¹⁸F]FAPI-74 PET imaging was successfully used to diagnose FAP expression, and as [²¹¹At]FAPI1 showed promising therapeutic efficacy in TNBC models, it is expected to be a viable therapeutic option. Full article

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. Full article

Background and Objectives: Thyroid ectopy represents a rare disease with an incidence of 0.3–1/100,000. It occurs due to the defective embryological process of the thyroid gland development. The thyroid ectopic tissue may suffer malignant transformation. This review aims to shed light on the roles that I-131 SPECT/CT (radioiodine 131 single-photon emission tomography fused with computed tomography) and F-18 PET/CT (fluorodeoxyglucose F18 positron emission tomography fused with computer tomography) may play in managing patients with ectopic thyroid carcinoma. Materials and Methods: A total number of 47 articles were identified on the PubMed and Google Scholar databases, and 3 other articles were selected from articles identified in the references cited in the retrieved articles. After refining the selection, the inclusion and exclusion criteria were applied, resulting in 10 articles that were included in the review. Results: The cases of ectopy included in this review were localised as follows: four cases in the thyroglossal duct, two cases in the mediastinum, one case in the oesophagus, one case in the thorax, one case with a pre-tracheal location, and one case with a latero-cervical location. In all the cases, F-18 FDG PET/CT was used as a diagnostic tool. In one case, F-18 FDG PET/CT was combined with I-131 SPECT/CT and MRI (magnetic resonance imaging). In one case, it was combined with 68 Ga-FAPI PET/CT (Ga-68 radiolabelled FAP inhibitor positron emission tomography fused with computer tomography). The maximum SUVs (standardised uptake values) ranged from 5.5 to 25 g/mL. Conclusions: F-18 PET/CT and I-131 SPECT/CT hybrid nuclear imaging is of great value in assessing ectopic thyroid carcinoma. F-18 FDG PET/CT plays an important role in the primary tumour evaluation and distant disease detection. Ga-68 FAPIs are a promising alternative. I-131 SPECT/CT adds important information related to the anatomical characterization of primary and distant iodine-avid lesions. Full article

Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy. All currently used FAPI rely on a linker–chelator complex attached to the ‘inhibitor’. We describe a new automated method of the direct attachment of the radioisotope to the inhibitor, resulting in a >50% MW reduction with the hope of an improved tumor-to-background ratio and tumor uptake. Methods: [¹⁸F]FluroFAPI was developed from a Sn precursor. This allowed for subsequent automated radioflourination. We obtained the biodistribution of [¹⁸F]FluroFAPI in rats, performed estimated human radiation dosimetry, and performed a 100× expected single dose toxicology analysis for eventual first-in-human experiments. Results: The synthesis of the Sn precursor for FluorFAPI and the automated synthesis of [¹⁸F]FluroFAPI was demonstrated. [¹⁸F]FluroFAPI had favorable estimated human radiation dosimetry, and demonstrated no adverse effects when injected at a dose of 100× that planned for [¹⁸F]FluroFAPI. Conclusions: With the successful development of an automated synthesis of [¹⁸F]FluroFAPI, first-in-human testing can be planned with the hope of an improved tumor-to-background performance compared to other FAPI agents. Full article

Purpose: This study aimed to evaluate the feasibility of using [⁶⁸Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing pulmonary fibrosis in a mouse model. We also examined its value in monitoring treatment response and compared it with traditional [¹⁸F]-fluorodeoxyglucose (FDG) PET and computed tomography (CT) imaging. Methods: A model of idiopathic pulmonary fibrosis was established using intratracheal injection of bleomycin (BLM, 2 mg/kg) into C57BL/6 male mice. For the treatment of IPF, a daily oral dose of 400 mg/kg/day of pirfenidone was administered from 9 to 28 days after the establishment of the model. Disease progression and treatment efficacy were assessed at different stages of the disease every week for four weeks using CT, [¹⁸F]FDG PET, and [⁶⁸Ga]FAPI PET (baseline imaging performed at week 0). Mice were sacrificed and lung tissues were harvested for hematoxylin-eosin staining, picrosirius red staining, and immunohistochemical staining for glucose transporter 1 (GLUT1) and FAP. Expression levels of GLUT1 and FAP in pathological sections were quantified. Correlations between imaging parameters and pathological quantitative values were analyzed. Results: CT, [¹⁸F]FDG PET and [⁶⁸Ga]FAPI PET revealed anatomical and functional changes in the lung that reflected progression of pulmonary fibrosis. In untreated mice with pulmonary fibrosis, lung uptake of [¹⁸F]FDG peaked on day 14, while [⁶⁸Ga]FAPI uptake and mean lung density peaked on day 21. In mice treated with pirfenidone, mean lung density and lung uptake of both PET tracers decreased. Mean lung density, [¹⁸F]FDG uptake, and [⁶⁸Ga]FAPI uptake correlated well with quantitative values of picrosirius red staining, GLUT1 expression, and FAP expression, respectively. Conclusions: Although traditional CT and [¹⁸F]FDG PET reflect anatomical and metabolic status in fibrotic lung, [⁶⁸Ga]FAPI PET provides a means of evaluating fibrosis progression and monitoring treatment response. Full article

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. Full article

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. Full article

(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. Full article

Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule ¹⁸F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, 12 and 13, were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC₅₀ 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [¹⁸F]fluoride exchange ([¹⁸F]SuFEx) reaction to furnish [¹⁸F]12 and [¹⁸F]13 in high activity yields (AY) of 39–56% and molar activities (A_m) between 20–55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and ¹⁸F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either ¹⁸F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [¹⁸F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development. Full article

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. Full article

In 2020, the Global Cancer Observatory estimated the incidence of colorectal cancer (CRC) at around 10.7% coupled with a mortality rate of 9.5%. The explanation for these values lies in the tumor microenvironment consisting of the extracellular matrix and cancer-associated fibroblasts (CAFs). Fibroblast activation protein (FAP) offers a promising target for cancer therapy since its functions contribute to tumor progression. Immunohistochemistry examination of FAP, fibronectin ED-B, and CXCR4 in primary tumors and their respective synchronous and/or metachronous metastases along with semiquantitative analysis have been carried out on histological samples of 50 patients diagnosed with metastatic CRC. The intensity of FAP, articulated by both “Intensity %” and “Intensity score”, is lower in the first metastasis compared to the primary tumor with a statistically significant correlation. No significant correlations have been observed regarding fibronectin ED-B and CXCR4. Tumors that produce FAP have an ambivalent relationship with this protein. At first, they exploit FAP, but later they reduce its expressiveness. Although our study has not directly included FAP-Inhibitor (FAPI) PET/CT, the considerable expression of FAP reveals its potential as a diagnostic and therapeutic tool worthy of further investigation. This dynamic relationship between cancer and FAP has substantial diagnostic and therapeutic implications. Full article