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In a recent contribution of Scott et al., the substrate scope of Cu-mediated nucleophilic radiofluorination with [18F]KF for the preparation of 18F-labeled arenes was extended to aryland vinylstannanes. Based on these findings, the potential of this reaction for the production of clinically relevant positron emission tomography (PET) tracers was investigated. To this end, Cu-mediated radiofluorodestannylation using trimethyl(phenyl)tin as a model substrate was re-evaluated with respect to different reaction parameters. The resulting labeling protocol was applied for 18F-fluorination of different electron-rich, -neutral and -poor arylstannyl substrates in RCCs of 16-88%. Furthermore, this method was utilized for the synthesis of 18F-labeled aromatic amino acids from additionally N-Boc protected commercially available stannyl precursors routinely applied for electrophilic radiohalogenation. Finally, an automated synthesis of 6-[18F]fluoro-L-m-tyrosine (6-[18F]FMT), 2-[18F]fluoro-L-tyrosine (2-[18F]F-Tyr), 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-[18F]FDOPA) and 3-O-methyl-6-[18F]FDOPA ([18F]OMFD) was established furnishing these PET probes in isolated radiochemical yields (RCYs) of 32-54% on a preparative scale. Remarkably, the automated radiosynthesis of 6-[18F]FDOPA afforded an exceptionally high RCY of 54 ± 5% (n = 5). [ABSTRACT FROM AUTHOR]

18F-Labeled aromatic amino acids exhibit great potential for diagnostic applications using positron emission tomography. However, the introduction of 18F into aromatic compounds remains challenging, and novel fluorination methods facilitating easy access to 18F-labeled arenes are highly sought after. In recent years, novel metal-mediated fluorination methods have been reported and transferred into radiochemistry. Based on Cu-mediated radiofluorination, a two-step synthesis of no-carrier-added (n.c.a.) 6-[18F]fluoro- l-tryptophan was developed. 6-[18F]Fluoro- l-tryptophan was synthesized with an overall radochemical yield of 16 ± 4% within 110 min and a specific activity of 280 GBq µmol-1. The radiochemical purity was more than 99 %. The developed method allowed access to radiofluorinated tryptophan derivatives in high radiochemical yields and opens new ways to provide radiofluorinated amino acids. Furthermore, the reaction conditions were optimized to facilitate automation. [ABSTRACT FROM AUTHOR]

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [ 68 Ga]Ga-fibroblast activation protein inhibitor (FAPI) ( 68 Ga-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 68 Ga-FAPI-46 and [ 18 F]FDG ( 18 F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUV max , 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 68 Ga-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 18 F-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 SUV max on 68 Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68 Ga-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 68 Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18 F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68 Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68 Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18 F-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 68 Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18 F-FDG PET/CT., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

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 68 Ga-FAPI PET/CT image interpretation. The aim of this study was to summarize common findings and report pitfalls in 68 Ga-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 SUV max , SUV mean , and SUV peak 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 SUV max 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 SUV max of 12.2 ± 7.3, and uptake correlated negatively with age (SUV max , r = -0.6, P < 0.01; SUV peak , r = -0.57, P < 0.01; SUV mean , r = -0.58, P < 0.01). Conclusion: Pitfalls include non-tumor-specific 68 Ga-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 68 Ga-FAPI PET/CT., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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., 68 Ga-FAPI-46) have shown high tumor uptake on PET in sarcoma patients. Here, we report the endpoints of the 68 Ga-FAPI PET prospective observational trial. Methods: Forty-seven patients with bone or soft-tissue sarcomas undergoing clinical 68 Ga-FAPI PET were eligible for enrollment into the 68 Ga-FAPI PET observational trial. Of these patients, 43 also underwent 18 F-FDG PET. The primary study endpoint was the association between 68 Ga-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 68 Ga-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 per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET-positive, 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 68 Ga-FAPI and 18 F-FDG PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients, 68 Ga-FAPI PET resulted in an upstaging compared with 18 F-FDG PET. 68 Ga-FAPI PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss κ: primary κ = 0.78, local nodal κ = 0.54, distant nodal κ = 0.91, lung κ = 0.86, bone κ = 0.69, and other κ = 0.65). Clinical management changed in 13 (30%) patients after 68 Ga-FAPI PET. Conclusion: We confirm an association between tumoral 68 Ga-FAPI PET uptake intensity and histopathologic FAP expression in sarcoma patients. Further, with masked readings and independent histopathologic validation, 68 Ga-FAPI PET had a high PPV and sensitivity for sarcoma staging., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

In a recent contribution of Scott et al., the substrate scope of Cu-mediated nucleophilic radiofluorination with [ 18 F]KF for the preparation of 18 F-labeled arenes was extended to aryl- and vinylstannanes. Based on these findings, the potential of this reaction for the production of clinically relevant positron emission tomography (PET) tracers was investigated. To this end, Cu-mediated radiofluorodestannylation using trimethyl(phenyl)tin as a model substrate was re-evaluated with respect to different reaction parameters. The resulting labeling protocol was applied for 18 F-fluorination of different electron-rich, -neutral and -poor arylstannyl substrates in RCCs of 16-88%. Furthermore, this method was utilized for the synthesis of 18 F-labeled aromatic amino acids from additionally N -Boc protected commercially available stannyl precursors routinely applied for electrophilic radiohalogenation. Finally, an automated synthesis of 6-[ 18 F]fluoro-l- m -tyrosine (6-[ 18 F]FMT), 2-[ 18 F]fluoro-l-tyrosine (2-[ 18 F]F-Tyr), 6-[ 18 F]fluoro-l-3,4-dihydroxyphenylalanine (6-[ 18 F]FDOPA) and 3- O -methyl-6-[ 18 F]FDOPA ([ 18 F]OMFD) was established furnishing these PET probes in isolated radiochemical yields (RCYs) of 32-54% on a preparative scale. Remarkably, the automated radiosynthesis of 6-[ 18 F]FDOPA afforded an exceptionally high RCY of 54 ± 5% ( n = 5)., Competing Interests: The authors declare no conflict of interest.

Two novel methods for copper-mediated aromatic nucleophilic radiofluorination were recently reported. Evaluation of these methods reveals that, although both are efficient in small-scale experiments, they are inoperative for the production of positron emission tomography (PET) tracers. Since high base content turned out to be responsible for low radiochemical conversions, a "low base" protocol has been developed which affords (18)F-labeled arenes from diaryliodonium salts and aryl pinacol boronates in reasonable yields. Furthermore, implementation of our "minimalist" approach to the copper-mediated [(18)F]-fluorination of (mesityl)(aryl)iodonium salts allows the preparation of (18)F-labeled arenes in excellent RCCs. The novel radiofluorination method circumvents time-consuming azeotropic drying and avoids the utilization of base and other additives, such as cryptands. Furthermore, this procedure enables the production of clinically relevant PET tracers; [(18)F]FDA, 4-[(18)F]FPhe, and [(18)F]DAA1106 are obtained in good isolated radiochemical yields. Additionally, [(18)F]DAA1106 has been evaluated in a rat stroke model and demonstrates excellent potential for visualization of translocator protein 18 kDa overexpression associated with neuroinflammation after ischemic stroke., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)