Fibroblast Activation Protein Inhibitor Research Articles

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

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

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

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

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

FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2, labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were evaluated in PC3 xenografts. Biodistribution studies of [68Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [177Lu]Lu-DOTAGA.(SA.FAPi)2 was retained longer in CAFs. [68Ga]Ga-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.(SA.FAPi)2 displayed elevated lipophilicity and affinity for human serum proteins compared to [68Ga]Ga-DOTA.SA.FAPi and [177Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [68Ga]Ga-DOTAGA.(SA.FAPi)2 within 3 h compared to [68Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [68Ga]Ga-DOTAGA.(SA.FAPi)2 versus [68Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [177Lu]Lu-DOTAGA.(SA.FAPi)2 maintained a significant tumor uptake even after 96 h p.i. compared to [177Lu]Lu-DOTA.SA.FAPi. Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.

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

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

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

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

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

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

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

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

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

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

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

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

PET-MRI Imaging to assess severity and distribution of atrial fibrosis in atrial fibrillation

Abstract Background Atrial fibrosis is a major determinant of atrial fibrillation (AF) susceptibility and ablation targeting fibrotic areas to suppress AF revealed by magnetic resonance imaging (MRI) was considered a promising approach to treat persistent AF; however, its outcome has been disappointing. We sought to develop a new imaging modality to detect the severity and distribution of atrial fibrosis. Methods This study enrolled 19 healthy volunteers and 85 patients with various cardiovascular (CV) diseases of whom 22 had persistent AF. Each patient underwent 18F-labeled aluminum fluoride targeting fibroblast activation protein inhibitor (18F-AlF-FAPI)-positron emission tomography - magnetic resonance imaging (PET-MRI). Left atrial appendage tissue biopsied at 18F-FAPI-uptake positive and negative sites was stained with Masson trichome to detect fibrosis (N=10). We compared cardiac atrial 18F-AlF-FAPI-PET-MRI imaging among healthy individuals, patients without AF and patients with persistent AF as well as patients developing and not developing postoperative AF (POAF). Results Degree of fibrosis based on Masson staining was consistent with 18F-FAPI-uptake (P&amp;lt;0.05). Whereas 18F-FAPI uptake was essentially undetectable in healthy volunteers, in patients with CV diseases, 18F-FAPI uptake was present in all atrial chambers. Patients with persistent AF had the greatest and most widespread uptake (P&amp;lt;0.001), including left atrium (P=0.001), right atrium (P&amp;lt;0.001), left atrial appendage (P=0.007), right atrial appendage (P&amp;lt;0.001), and left atrial posterior wall (P=0.004). 18F-FAPI-uptake did not differ between those with versus without POAF. Conclusions 18F-AlF-FAPI-PET-MRI imaging detected atrial fibrosis in patients with various CV diseases; patients with persistent AF exhibit severe and widespread fibrosis, while POAF is not associated with increased 18F-FAPI uptake.

Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

FAPI PET uptake patterns after invasive medical interventions: a single center retrospective analysis.

Fibroblast activation protein (FAP)-inhibitor (FAPI)-PET tracers allow imaging of the FAP-expressing cancer associated fibroblasts (CAF) and also the normal activated fibroblasts (NAF) involved in inflammation/fibrosis that may be present after invasive medical interventions. We evaluated [68Ga]Ga-FAPI-46 uptake patterns post-medical/invasive non-systemic interventions. This single-center retrospective analysis was conducted in 79 consecutive patients who underwent [68Ga]Ga-FAPI-46 PET/CT. Investigators reviewed prior patient medical/invasive interventions (surgery, endoscopy, biopsy, radiotherapy, foreign body placement (FBP) defined as implanted medical/surgical material present at time of scan) and characterized the anatomically corresponding FAPI uptake intensity both visually (positive if above surrounding background) and quantitatively (SUVmax). Interventions with missing data/images or confounders of [68Ga]Ga-FAPI-46 uptake (partial volume effect, other cause of increased uptake) were excluded. Available correlative FDG, DOTATATE and PSMA PET/CTs were analyzed when available. 163 medical/invasive interventions (mostly surgeries (49%), endoscopies (18%) and non-surgical biopsies (10%)) in 60 subjects were included for analysis. 43/163 (26%) involved FBP. FAPI uptake occurred in 24/163 (15%) of interventions (average SUVmax 3.2 (mild), range 1.5-5.1). The median time-interval post-intervention to FAPI-PET was 47.5months and was shorter when FAPI uptake was present (median 9.5months) than when absent (median 60.1months; p = 0.001). Cut-off time beyond which no FAPI uptake would be present post-intervention without FBP was 8.2months, with a sensitivity, specificity, positive predictive value and negative predictive value of 82, 90, 99 and 31% respectively. No optimal cutoff point could be determined when considering interventions with FBP. No significant difference was detected between frequency of [68Ga]Ga-FAPI-46 and [18F]FDG uptake in intervention sites. Compared to [68Ga]Ga-PSMA-11, [68Ga]Ga-FAPI-46 revealed more frequent and intense post-interventional tracer uptake. [68Ga]Ga-FAPI-46 uptake from medical/invasive interventions without FBP appears to be time dependent, nearly always absent beyond 8months post-intervention, but frequently present for years with FBP.

Non-specific uptake of 18F-FAPI-04 in the pancreas and its related factors: a post-hoc analysis of an ongoing prospective clinical trial

This study aimed to analyze the characteristics of the non-specific uptake (NSU) of 18F-labeled fibroblast activation protein inhibitor (18F-FAPI) of the pancreas and investigate the related factors. Totally, 78 patients who underwent both 18F-fluorodeoxyglucose (FDG) and 18F-FAPI PET/CT examinations were divided into normal (n = 53) and NSU (n = 25) groups. The differences in general information, medical history, laboratory indexes and uptake were compared. Receiver operating characteristic (ROC) curves were used to analyze the optimal cut-off values. The correlations between 18F-FAPI-SUVmax and blood cell analysis, liver function indexes, tumor markers, and inflammatory indices were analyzed. The logistic regression model was used to estimate the independent factors. Both 18F-FAPI (4.48 ± 0.98 vs. 2.01 ± 0.53, t = 11.718, P < 0.05) and 18F-FDG (2.23 ± 0.42 vs. 2.02 ± 0.44, t = 2.036, P = 0.045) showed significantly higher in NSU group. Patients in the NSU group tended to be complicated with a history of drinking (P = 0.034), chronic liver diseases (P = 0.006), and surgery of gastrectomy (P = 0.004). ROC analysis showed cutoff values of 3.25 and 2.05 for 18F-FAPI and 18F-FDG in identifying the NSU. Patients in the NSU group showed less platelet count, higher platelet volume, higher total bilirubin, direct or indirect bilirubin (P < 0.05). Platelet count, platelet crit, large platelet ratio, aspartate aminotransferase (AST), α-l-fucosidase, and total, direct or indirect bilirubin were correlated with 18F-FAPI-SUVmax (P < 0.05). AST [1.099 (1.014, 1.192), P = 0.021] and total bilirubin [1.137 (1.035, 1.249), P = 0.007] were two independent factors in the step forward logistic regression, and platelet/% [1.079 (1.004, 1.160), P = 0.039] and total bilirubin [1.459 (1.016, 2.095), P = 0.041] were two independent factors in the step backward logistic regression for the prediction of pancreatic uptake of 18F-FAPI. 18F-FAPI-PET/CT was better than 18F-FDG in predicting the pancreatic NSU, and NSU is related to a history of drinking, chronic liver diseases, gastrectomy, heteromorphic platelet, and impaired liver function.

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&amp;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&amp;lt; 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 &amp;lt; 0.05) and US (P &amp;lt; 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 &amp;gt; 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&amp;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.