Purpose of the Report:Combined cardiac 68Ga-Fibroblast-Activation Protein-alpha inhibitor (FAPI) positron-emission tomography (PET) and cardiac magnetic resonance imaging (MRI) constitute a novel diagnostic tool in patients for the assessment of myocardial damage after an acute myocardial infarction (AMI). Purpose of this pilot study was to evaluate simultaneous Ga-68-FAPI-46-PET/MR imaging in the delayed phase after AMI. Material and Methods:Eleven patients underwent hybrid 68Ga-FAPI-46 PET/MRI post AMI. Standardized uptake values and fibroblast activation volume (FAV) were calculated and correlated with serum biomarkers and MRI parameters. Results:Significant 68Ga-FAPI-46 uptake could be demonstrated in 11 (100 %) patients after a mean period of 30.9 ± 22.0 days. FAV significantly exceeded the infarction size in MRI and showed a good correlation to MRI parameters as well as to serum biomarkers of myocardial damage. Conclusions:68Ga-FAPI-46 PET/MRI offers molecular and morphological imaging of affected myocardium after AMI. This study demonstrates ongoing fibroblast activation in a delayed phase after AMI and generates hypotheses for future studies while aiming for a better understanding of myocardial remodeling following ischemic tissue damage.

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.

FAPI-PET/CT exhibits high tumor uptake and low background accumulation, enabling high-sensitivity tumor detection. We compared the diagnostic performance of 68 Ga-FAPI-46 PET/CT plus contrast-enhanced CT (CE-CT), 18F-FDG PET/CT plus CE-CT, and standalone CE-CT in patients with various malignancies. 232 patients underwent 68 Ga-FAPI-46 PET/CT,18F-FDG PET/CT, and CE-CT each within 4 weeks. Detection rates were assessed by a blinded reader, with ≥ 2 weeks between scans of the same patient to avoid recall bias. A sub-analysis of diagnostic performance was performed for 490 histopathologically validated lesions. Detection rates were compared using McNemar’s test. Lesion-based detection rates in 68 Ga-FAPI-46 PET/CT plus CE-CT, 18F-FDG PET/CT plus CE-CT, and CE-CT alone were 91.2

Ziel/Aim SFTs are rare mesenchymal tumors frequently diagnosed late due to delayed occurrence of symptoms. Localized tumors are mostly treated by resection, while there is no effective standard treatment for advanced, metastatic stages. Hence, accurate imaging is essential, especially due to detection limits of current imaging modalities. Therefore, we aim to assess accuracy and impact on management of Ga-68-FAPI-46 PET.

The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein–protein interactions in cardiovascular diseases remains a challenging task in drug development. This study investigates whether a non-specific cell-targeted peptide drug is available in a timely manner at its intended biological destination, the heart, using a combined stepwise nuclear molecular imaging approach. An octapeptide (heart8P) was covalently coupled with the trans-activator of transcription (TAT) protein transduction domain residues 48–59 of human immunodeficiency virus-1 (TAT-heart8P) for efficient internalization into mammalian cells. The pharmacokinetics of TAT-heart8P were evaluated in dogs and rats. The cellular internalization of TAT-heart8P-Cy(5.5) was examined on cardiomyocytes. The real-time cardiac delivery of 68Ga-NODAGA-TAT-heart8P was tested in mice under physiological and pathological conditions. Pharmacokinetic studies of TAT-heart8P in dogs and rats revealed a fast blood clearance, high tissue distribution, and high extraction by the liver. TAT-heart-8P-Cy(5.5) was rapidly internalized in mouse and human cardiomyocytes. Correspondingly, organ uptake of hydrophilic 68Ga-NODAGA-TAT-heart8P occurred rapidly after injection with an initial cardiac bioavailability already 10 min post-injection. The saturable cardiac uptake was revailed by the pre-injection of the unlabeled compound. The cardiac uptake of 68Ga-NODAGA-TAT-heart8P did not change in a model of cell membrane toxicity. This study provides a sequential stepwise workflow to evaluate the cardiac delivery of a hydrophilic, non-specific cell-targeting peptide. 68Ga-NODAGA-TAT-heart8P showed rapid accumulation in the target tissue early after injection. The implementation of PET/CT radionuclide-based imaging methodology as a means to assess effective and temporal cardiac uptake represents a useful and critical application in drug development and pharmacological research and can be extended to the evaluation of comparable drug candidates.

Corentin Warnier, Thibault Gendron, Muhammad Otabashi, Charles Vriamont and Alex Jackson were not included as authors in the original publication [...].

Purpose: The aim of this study was to investigate conditions for reliable quantification of sub-centimeter lesions with low F-18, Ga-68, and I-124 uptake using a silicon photomultiplier-based PET/CT system. Methods: A small tumor phantom was investigated under challenging but clinically realistic conditions resembling prostate and thyroid cancer lymph node metastases (6 spheres with 3.7-9.7 mm in diameter, 9 different activity concentrations ranging from about 0.25-25 kBq/mL, and a signal-to-background ratio of 20). Radionuclides with different positron branching ratios and prompt gamma coincidence contributions were investigated. Maximum-, contour-, and oversize-based partial volume effect (PVE) correction approaches were applied. Detection and quantification performance were estimated, considering a +/- 30 % deviation between imaged-derived and true activity concentrations as acceptable. A standard and a prolonged acquisition time and two image reconstruction algorithms (time-of-flight with/without point spread function modelling) were analyzed. Clinical data were evaluated to assess agreement of PVE-correction approaches indicating lesion quantification validity. Results: The smallest 3.7-mm sphere was not visible. If the lesions were clearly observed, quantification was, except for a few cases, acceptable using contour- or oversized-based PVE-corrections. Quantification accuracy did not substantially differ between F-18, Ga-68, and I-124. No systematic differences between the analyzed reconstruction algorithms or shorter and larger acquisition times were observed. In the clinical evaluation of 20 lesions, an excellent statistical agreement between oversize- and contour-based PVE-corrections was observed. Conclusions: At the lower end of size (<10 mm) and activity concentration ranges of lymph-node metastases, quantification with reasonable accuracy is possible for F-18, Ga-68, and I-124, possibly allowing pre-therapeutic lesion dosimetry and individualized radionuclide therapy planning.

[18F]PARPi is currently undergoing clinical trials as a PET tracer for many applications. However, only manual radiosynthesis was reported; this has several drawbacks, including an increased risk of contamination from the operator, and the need to limit the starting activity. The automation of the previously reported protocol for [18F]PARPi synthesis is challenging, as it requires transferring microvolumes of reagents, which many platforms cannot accommodate. We report a revised, high yield, and automated protocol for the radiosynthesis of [18F]PARPi, with final doses of over 20 GBq.

The NETTER-1, VISION, and TheraP trials proved the efficacy of repeat intravenous application of small radioligands. Application by subcuta-neous, intraperitoneal, or oral routes is an important alternative and may yield comparable or favorable organ and tumor radioligand uptake. Here, we assessed organ and tumor biodistribution for various radioligand application routes in healthy mice and models of cancer expressing somatostatin receptor (SSTR), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP). Methods: Healthy and tumor-bearing male C57BL/6 or NOD SCID y-mice, respectively, were administered a mean of 6.0 ?? 0.5 MBq of 68Ga-DOTATOC (RM1-SSTR allograft), 5.3 ?? 0.3 MBq of 68Ga-PSMA11 (RM1-PSMA allograft), or 4.8 ?? 0.2 MBq of 68Ga-FAPI46 (HT1080-FAP xenograft) by intravenous, intraperitoneal, subcutaneous, or oral routes. In vivo PET images and ex vivo biodistribution in tumor, organs, and the injection site were assessed up to 5 h after injection. Healthy mice were monitored for up to 7 d after the last scan for signs of stress or adverse reactions. Results: After intravenous, intraperito-neal, and subcutaneous radioligand administration, average residual activity at the injection site was less than 17 percentage injected activity per gram (%IA/g) at 1 h after injection, less than 10 %IA/g at 2 h after injection, and no more than 4 %IA/g at 4 h after injection for all radioligands. After oral administration, at least 50 %IA/g remained within the intestines until 4 h after injection. Biodistribution in organs of healthy mice was nearly equivalent after intravenous, intraperito-neal, and subcutaneous application at 1 h after injection and all sub-sequent time points (???1 %IA/g for liver, blood, and bone marrow; 11.2 ?? 1.4 %IA/g for kidneys). In models for SSTR-, PSMA-and FAP-expressing cancer, tumor uptake was increased or equivalent for intraperitoneal/subcutaneous versus intravenous injection at 5 h after injection (ex vivo): SSTR, 7.2 ?? 1.0 %IA/g (P = 0.0197)/6.5 ?? 1.3 %IA/g (P = 0.0827) versus 2.9 ?? 0.3 %IA/g, respectively; PSMA, 3.4 ?? 0.8 %IA/g (P = 0.9954)/3.9 ?? 0.8 %IA/g (P = 0.8343) versus 3.3 ?? 0.7% IA/g, respectively; FAP, 1.1 ?? 0.1 %IA/g (P = 0.9805)/ 1.1 ?? 0.1 %IA/g (P = 0.7446) versus 1.0 ?? 0.2 %IA/g, respectively. Conclusion: In healthy mice, biodistribution of small theranostic ligands after intraperitoneal/subcutaneous application is nearly equivalent to that after intravenous injection. Subcutaneous administra-tion resulted in the highest absolute SSTR tumor and tumor-to-organ uptake as compared with the intravenous route, warranting further clinical assessment.

Fibroblast activation protein inhibitor (FAPI) PET/CT is a new tool in the diagnostic workup of cancer. With a growing volume of applications, pitfalls and common findings need to be considered for 68Ga-FAPI PET/CT image interpretation. The aim of this study was to summarize common findings and report pitfalls in 68Ga-FAPI PET/CT. Methods: Ninety-one patients underwent whole-body PET/CT with either FAPI-04 (n = 25) or FAPI-46 (n = 66). Findings were rated in a consensus session of 2 experienced readers. Pitfalls and common findings were defined as focal or localized uptake above the background level and categorized as unspecific or nonmalignant and grouped into degenerative, muscular, scarring/wound-healing, uterine, mammary gland, and head-and-neck findings. The frequency of findings was reported on a per-patient and per-group basis, and SUVmax, SUVmean, and SUVpeak were measured. Results: Non-tumor-specific uptake was found in 81.3% of patients. The most frequent finding was uptake in degenerative lesions (51.6%), with a mean SUVmax of 7.7 ± 2.9, and head-and-neck findings (45.1%). Except for the salivary glands, the uptake values did not differ between 10 and 60 min after injection in most findings. Uterine uptake was found in most women (66.7%), with a mean SUVmax of 12.2 ± 7.3, and uptake correlated negatively with age (SUVmax, r = -0.6, P < 0.01; SUVpeak, r = -0.57, P < 0.01; SUVmean, r = -0.58, P < 0.01). Conclusion: Pitfalls include non-tumor-specific 68Ga-FAPI uptake in degenerative lesions, muscle, the head and neck, scarring, the mammary glands, or the uterus. Here, we summarize the findings to help readers avoid common mistakes at centers introducing 68Ga-FAPI PET/CT.

Introduction: With respect to the broad application of FAPI-46 in therapy and diagnostics, there is a need for an efficient as well as convenient way for routine production and quality control of the theranostic pair [90Y]Y/ [68Ga]Ga-FAPI-46, since no monograph is currently available for radiolabelled FAPI derivatives. The aim of the current work is to create a GMP compliant theranostic set up for the production and quality control of the diagnostic [68Ga]Ga-FAPI-46 as well as the therapeutic drug [90 Y]Y-FAPI-46, which can be the basis for future monographic standards. Methods: Sterile [90Y]yttrium chloride solution and a pharmaceutical grade 68Ge/68Ga generator were applied for the labelling of FAPI-46 using the cassette based synthesis module Trasis EASYONE. All chemicals were GMPgrade and excipients were with marketing authorisation. The quality control included test procedures according to Ph. Eur. Results: Fully automated synthesis of the theranostic pair [90Y]Y/[68Ga]Ga-FAPI-46 was achieved on the Trasis EasyOne synthesizer with a radiochemical yield of 88 & PLUSMN; 7% and 56 +/- 5% with a radiochemical purity of > 99%. Stability experiments showed a durability for [68Ga]Ga-FAPI-46 within 4 h and for [90Y]Y-FAPI-46 within 24 h. All obtained specifications and validations were compliant with the European Pharmacopoeia and regulatory guidelines. Both products were successfully applied in cancer patients. Conclusion: In the present work, efficient and robust procedures for the automated production and quality control of the theranostic pair [68Ga]/[90Y]FAPI 46 were developed and validated using the same synthetic platform. The described methods were evaluated in accordance with existing guidelines and toxicological limits, which can be a valuable basis for future monographic standards.

Abstract Background New-generation silicon-photomultiplier (SiPM)-based PET/CT systems exhibit an improved lesion detectability and image quality due to a higher detector sensitivity. Consequently, the acquisition time can be reduced while maintaining diagnostic quality. The aim of this study was to determine the lowest 18F-FDG PET acquisition time without loss of diagnostic information and to optimise image reconstruction parameters (image reconstruction algorithm, number of iterations, voxel size, Gaussian filter) by phantom imaging. Moreover, patient data are evaluated to confirm the phantom results. Methods Three phantoms were used: a soft-tissue tumour phantom, a bone-lung tumour phantom, and a resolution phantom. Phantom conditions (lesion sizes from 6.5 mm to 28.8 mm in diameter, lesion activity concentration of 15 kBq/mL, and signal-to-background ratio of 5:1) were derived from patient data. PET data were acquired on an SiPM-based Biograph Vision PET/CT system for 10 min in list-mode format and resampled into time frames from 30 to 300 s in 30-s increments to simulate different acquisition times. Different image reconstructions with varying iterations, voxel sizes, and Gaussian filters were probed. Contrast-to-noise-ratio (CNR), maximum, and peak signal were evaluated using the 10-min acquisition time image as reference. A threshold CNR value ≥ 5 and a maximum (peak) deviation of ± 20% were considered acceptable. 20 patient data sets were evaluated regarding lesion quantification as well as agreement and correlation between reduced and full acquisition time standard uptake values (assessed by Pearson correlation coefficient, intraclass correlation coefficient, Bland–Altman analyses, and Krippendorff’s alpha). Results An acquisition time of 60 s per bed position yielded acceptable detectability and quantification results for clinically relevant phantom lesions ≥ 9.7 mm in diameter using OSEM-TOF or OSEM-TOF+PSF image reconstruction, a 4-mm Gaussian filter, and a 1.65 × 1.65 x 2.00-mm3 or 3.30 × 3.30 x 3.00-mm3 voxel size. Correlation and agreement of patient lesion quantification between full and reduced acquisition times were excellent. Conclusion A threefold reduction in acquisition time is possible. Patients might benefit from more comfortable examinations or reduced radiation exposure, if instead of the acquisition time the applied activity is reduced.

•Streamlined automated production of [68Ga]Ga-pentixafor.•Increased [68Ga]Ga-pentixafor yield by application of a Multi Generator Tool.•Reduced synthesis time of 14,5 min.•Significant reduction of ethanol content (3,5 ± 0.5 mg/mL).

Bone and soft-tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblasts. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radiolabeled FAP inhibitors (e.g., 68Ga-FAPI-46) have shown high tumor uptake on PET in sarcoma patients. Here, we report the endpoints of the 68Ga-FAPI PET prospective observational trial. Methods: Forty-seven patients with bone or soft-tissue sarcomas undergoing clinical 68Ga-FAPI PET were eligible for enrollment into the 68Ga-FAPI PET observational trial. Of these patients, 43 also underwent 18F-FDG PET. The primary study endpoint was the association between 68Ga-FAPI PET uptake intensity and histopathologic FAP expression analyzed with Spearman r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI PET uptake intensity and histopathologic FAP expression was significant (Spearman r = 0.43; P = 0.03). By histopathologic validation, PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a perregion basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PETpositive, resulting in an SE of 0.96 (95% CI, 0.82-1.00) on a per-patient and 0.94 (95% CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in 68Ga-FAPI and 18F-FDG PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients, 68Ga-FAPI PET resulted in an upstaging compared with 18F-FDG PET. 68Ga-FAPI PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss K: primary K = 0.78, local nodal K = 0.54, distant nodal K = 0.91, lung K = 0.86, bone K = 0.69, and other K = 0.65). Clinical management changed in 13 (30%) patients after 68Ga-FAPI PET. Conclusion: We sity and histopathologic FAP expression in sarcoma patients. Further, with masked readings and independent histopathologic validation,

Positron emission tomography (PET) using small ligands of the fibroblast activation protein (FAP) was recently introduced. However, optimal uptake time has not been defined yet. Here, we systematically compare early (~ 10 min p.i.) and late (~ 60 min p.i.) FAPI-46 imaging in patients with various types of cancer. This is a retrospective single-institutional study. Imaging was performed at the Essen University Hospital, Germany. A total of 69 patients who underwent dual time-point imaging for either restaging (n = 52, 75%) or staging (n = 17, 25%) of cancer were included. Patients underwent PET with two acquisitions: early (mean 11 min, SD 4) and late (mean 66 min, SD 9). Mean injected activity was 148 MBq (SD 33). In total, 400 lesions were detected in 69 patients. Two of 400 (0.5%) lesions were only seen in early time-point imaging but not in late time-point imaging. On a per-patient level, there was no significant difference between SUVmax of hottest tumor lesions (Wilcoxon: P = 0.73). Organ uptake demonstrated significant early to late decrease in SUVmean (average ∆SUVmean: − 0.48, − 0.14, − 0.27 for gluteus, liver, and mediastinum, respectively; Wilcoxon: P < 0.001). On a per-lesion basis, a slight increase of SUVmax was observed (average ∆SUVmax: + 0.4, Wilcoxon: P = 0.03). In conclusion, early (~ 10 min p.i.) versus late (~ 60 min p.i.) FAPI-46 imaging resulted in equivalent lesion uptake and tumor detection. For improved feasibility and scan volume, we implement early FAPI-46 PET in future clinical and research protocols.

Ziel/Aim Positron-Emission-Tomography (PET) using small-ligands of the fibroblast activation protein (FAP) was recently introduced. However, the optimal uptake time was not defined yet. Here, we systematically compare early (~ 10 min p.i.) and late (~ 60 min p.i.) FAPI-46 imaging in patients with various cancers.

Ziel/Aim With growing theranostic applications and translational research, small animal models need to be optimized for feasible and tolerable repeated small ligand application. Here we aim to assess application routes s.c., i.p. and p.o. as alternative to i.v. application in healthy mice and models of PSMA, SSTR and FAPI-expressing cancer.