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Introduction: Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) that is able to inhibit the EGFR treatment resistance mutation T790M and primary EGFR mutations Del19 and L858R. The aim of the study was to evaluate the potential of carbon-11 labeled osimertinib to be used as a tracer for the PET imaging of tumors bearing the T790M mutation., Methods: Osimertinib was labeled with carbon-11 at two positions, and the effect of the labeling position on the metabolism and biodistribution was studied in female nu/nu mice. The mutation status specificity of osimertinib was confirmed in vitro in a cell growth inhibition experiment, and the tumor-targeting potential of the carbon-11 isotopologues was evaluated using female nu/nu mice xenografted with NSCLC cell lines; the wild-type EGFR expressing A549, the primary Del19 EGFR mutated HCC827 and the resistance T790M/L858R mutated H1975. One of the osimertinib tracers was selected based on the results acquired and evaluated for tracer specificity and selectivity by assessment of tumor uptake in a PET study where HCC827 tumor-bearing mice were pretreated with osimertinib or afatinib., Results: [Methylindole- 11 C]- and [dimethylamine- 11 C]osimertinib were synthesized by 11 C-methylation of precursors AZ5104 and AZ7550, respectively. Rapid metabolism of both analogs of [ 11 C]osimertinib was observed. Although the tumor uptake and retention of [methylindole- 11 C]- and [dimethylamine- 11 C]osimertinib in tumors were similar, the tumor-to-muscle ratios appeared to be higher for [methylindole- 11 C]osimertinib. The highest uptake, tumor-to-blood, and tumor-to-muscle ratio were observed in the Del19 EGFR mutated HCC827 tumors. However, the specificity and selectivity of [methylindole- 11 C]osimertinib PET could not be demonstrated in HCC827 tumors. The uptake of [methylindole- 11 C]osimertinib was not significantly higher in T790M resistance mutated H1975 xenografts compared to the negative control cell line A549., Conclusions: Osimertinib was successfully labeled at two positions with carbon-11, yielding two EGFR PET tracers, [methylindole- 11 C]osimertinib and [dimethylamine- 11 C]osimertinib. The preclinical evaluation demonstrated uptake and retention in three NSCLC xenografts; A549, HCC827, and H1975. The highest uptake was observed in the primary Del19 EGFR mutated HCC827. The ability of [methylindole- 11 C]osimertinib to distinguish between the T790M resistance mutated H1975 xenografts and the wild-type EGFR expressing A549 could not be confirmed in the ex vivo study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.D. Windhorst is editor-in-chief of Nuclear Medicine & Biology. Daniëlle A.M. Heideman is a minority shareholder of Self-screen B.V., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The transforming growth factor β (TGFβ) pathway plays a complex role in cancer biology, being involved in both tumour suppression as well as promotion. Overactive TGFβ signalling has been linked to multiple diseases, including cancer, pulmonary arterial hypertension, and fibrosis. One of the key meditators within this pathway is the TGFβ type I receptor, also termed activin receptor-like kinase 5 (ALK5). ALK5 expression level is a key determinant of TGFβ signalling intensity and duration, and perturbation has been linked to diseases. A validated ALK5 positron emission tomography (PET) tracer creates an opportunity, therefore, to study its role in human diseases. To develop ALK5 PET tracers, two small molecule ALK5 kinase inhibitors were selected as lead compounds, which were labelled with carbon-11 and fluorine-18, respectively. [ 11 C]LR111 was synthesized with a yield of 17 ± 6%, a molar activity of 126 ± 79 GBq·μmol -1 and a purity of >95% (n = 44). [ 18 F]EW-7197 was synthesized with a yield of 10 ± 5%, a molar activity of 183 ± 126 GBq·μmol -1 and a purity of >95% (n = 11). Metabolic stability was evaluated in vivo in mice, showing 39 ± 2% of intact [ 11 C]LR111 and 21 ± 2% of intact [ 18 F]EW-7197 in blood plasma at 45 min p.i. In vitro binding experiments were conducted in breast cancer MDA-MB-231 and lung cancer A431 cell lines. In addition, both tracers were used for PET imaging in MDA-MB-231 xenograft models. Selective uptake of [ 18 F]EW-7197 and [ 11 C]LR111 was observed in MDA-MB-231 cells, in the MDA-MB-231 tumour xenografts in vivo and in the autoradiograms. As [ 11 C]LR111 and [ 18 F]EW-7197 showed selectivity of binding to ALK5 in vivo and in vitro. Both tracers are thereby valuable tools for the detection of ALK5 activity., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the parathyroid glands is the standard treatment but requires precise pre-operative localization of the glands. However, currently available imaging modalities show limited sensitivity. Since positron emission tomography (PET) is a molecular imaging technique with high accuracy and sensitivity, our aim was to develop a new PET tracer for overactive parathyroid glands imaging by radiolabelling cinacalcet, a drug binding to the calcium-sensing receptor of the parathyroid glands., Methods: [ 18 F]Cinacalcet was synthesized by copper-catalysed [ 18 F]trifluoromethylation of a boronic acid precursor using high molar activity [ 18 F]fluoroform. Ex vivo biodistribution and metabolism were evaluated in 12 healthy male Wistar rats at 5, 15, 45 and 90 min. PET scans were performed at baseline and after blocking with NPS R-568., Results: [ 18 F]Cinacalcet was obtained in an overall radiosynthesis time of 1 h with a radiochemical purity of 98 ± 1%, a radiochemical yield of 8 ± 4% (overall, n = 7, corrected for decay) and a molar activity of 40 ± 11 GBq/μmol (n = 7, at EOS). The ex vivo biodistribution showed uptake in the thyroid and parathyroid glands as well as in other glands such as adrenals, salivary glands and pancreas. The tracer was rapidly cleared from the blood via liver and kidneys and showed fast metabolism. PET images confirmed uptake in the target organ. However, in a blocking study with NPS R-568 specific binding of [ 18 F]cinacalcet to the CaSR could not be confirmed., Conclusions: [ 18 F]Cinacalcet was successfully synthesized. First in vivo experiments in healthy rats showed uptake of the tracer in the target organ and fast metabolism, encouraging further in vivo evaluation of this tracer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Albert D. Windhorst, co-author of this manuscript, is editor-in-chief of Nuclear Medicine and Biology. He was not involved in the review process of this manuscript to avoid any potential conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)