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[13N]Ammonia is one of the most commonly used Positron Emission Tomography (PET) radiotracers in humans to assess myocardial perfusion and measure myocardial blood flow. Here, we report a reliable semi-automated process to manufacture large quantities of [13N]ammonia in high purity by proton-irradiation of a 10 mM aqueous ethanol solution using an in-target process under aseptic conditions. Our simplified production system is based on two syringe driver units and an in-line anion-exchange purification for up to three consecutive productions of ~30 GBq (~800 mCi) (radiochemical yield = 69 ± 3% n.d.c) per day. The total manufacturing time, including purification, sterile filtration, reformulation, and quality control (QC) analyses performed before batch release, is approximately 11 min from the End of Bombardment (EOB). The drug product complies with FDA/USP specifications and is supplied in a multidose vial allowing for two doses per patient, two patients per batch (4 doses/batch) on two separate PET scanners simultaneously. After four years of use, this production system has proved to be easy to operate and maintain at low costs. Over the last four years, more than 1000 patients have been imaged using this simplified procedure, demonstrating its reliability for the routine production of large quantities of current Good Manufacturing Practices (cGMP)-compliant [13N]ammonia for human use. [ABSTRACT FROM AUTHOR]

Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo‐endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O‐11C‐methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)‐5‐(Biphenyl‐4‐yl)‐4‐[(3‐carboxypropionyl)amino]‐2‐methylpentanoic acid [11C]methyl ester ([11C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11C‐methyl instead of an ethyl. [11C]MeOLBQ was produced in a one‐pot two‐step synthesis. The O‐11C‐methylation of the pentanoic acid part was done with [11C]methyl triflate followed by the deprotection of the tert‐butyl ester precursor in acidic conditions. [11C]MeOLBQ ([11C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay‐corrected from [11C]CO2, n = 3) high molar activity 348 ± 100 GBq/μmol (9425 ± 2720 mCi/μmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET‐labeled analog of the clinically used NEP inhibitor sacubitril. [ABSTRACT FROM AUTHOR]

[18F]DCFPyL is a clinical‐stage PET radiotracer used to image prostate cancer. This report details the efficient production of [18F]DCFPyL using single‐step direct radiofluorination, without the use of carboxylic acid‐protecting groups. Radiolabeling reaction optimization studies revealed an inverse correlation between the amount of precursor used and the radiochemical yield. This simplified approach enabled automated preparation of [18F]DCFPyL within 28 minutes using HPLC purification (26% ± 6%, at EOS, n = 4), which was then scaled up for large‐batch production to generate 1.46 ± 0.23 Ci of [18F]DCFPyL at EOS (n = 7) in high molar activity (37 933 ± 4158 mCi/μmol, 1403 ± 153 GBq/μmol, at EOS, n = 7). Further, this work enabled the development of [18F]DCFPyL production in 21 minutes using an easy cartridge‐based purification (25% ± 9% radiochemical yield, at EOS, n = 3). [ABSTRACT FROM AUTHOR]

Background: The free-fatty acid receptor-1 (FFA-1) is expressed by β-cells and is a promising target for molecular imaging of functional β-cell mass. Recently, the ((3-[18F]fluoropropyl)sulfonyl)propoxy-derivative of the high-affinity FFA-1 agonist TAK-875 ([18F]7) was reported. Here we describe the preparation of this tracer in high molar activity using a purification method permitting separation of [18F]7 from a structurally-related by-product and evaluation of the tracer in rats as a potential FFA-1 PET imaging agent.Results: The radiotracer was produced by nucleophilic radio-fluorination of the tosylate precursor and deprotection of the methyl ester. Semi-preparative HPLC with a C18 column revealed that [18F]7 co-eluted with a non-radioactive impurity. Mass spectrometry identified the impurity as the alkene-containing elimination by-product. A pentafluorophenyl-functionalized HPLC column was found to separate the two compounds and allowed for purification of [18F]7 in high molar activity. A strong anion-exchange resin was used to reformulate [18F]7 in high concentration. Starting from 96 to 311 GBq of [18F]fluoride, 3.8-15.4 GBq of pure [18F]7 (end of synthesis (EOS)) was prepared (RCY 8.3% ± 1.1% decay-corrected, n = 4) in high molar activity (166-767 GBq/μmol at EOS). This PET agent was evaluated in rats using dynamic microPET/CT imaging, ex vivo biodistribution, and radio-metabolite studies. MicroPET/CT exhibited high uptake of the tracer in the abdominal area. There was no measurable decrease of the PET signal in the pancreatic area in rats pre-treated with saturating doses (30 mg/kg) of TAK-875. Biodistribution studies corroborated the microPET/CT results. Radiometabolism analyses revealed high compound stability with only the parent molecule detected in the pancreas.Conclusions: Analysis of the crude reaction mixture and identification of the elimination by-product allowed for the development of a fully automated process to prepare the TAK-875-derived PET agent [18F]7 in high purity and high molar activity. Even though the radiotracer exhibited high in vivo stability, microPET/CT and biodistribution results confirmed recent reports demonstrating that lipophilic analogs of TAK-875 display a high degree of non-specific binding, masking any specific binding to FFA-1 in pancreatic β-cells. Future development of TAK-875-derived PET tracers should focus on reducing non-specific binding in the pancreatic tissue. [ABSTRACT FROM AUTHOR]

The serine/threonine kinase B-Raf is an essential regulator of cellular growth, differentiation, and survival. B-Raf protein expression is elevated throughout melanoma progression, making it an attractive target for noninvasive imaging using positron-emission tomography. Encorafenib is a potent and highly selective inhibitor of B-Raf used in the clinical management of melanoma. In this study, the radiosynthesis of a 11 C-isotopologue of encorafenib was developed using an in-loop [ 11 C]CO 2 fixation reaction. Optimization of reaction conditions reduced the formation of a radiolabeled side product and improved the isolated yields of [ 11 C]encorafenib (14.5 ± 2.4% radiochemical yield). The process was fully automated using a commercial radiosynthesizer for the production of 6845 ± 888 MBq of [ 11 C]encorafenib in high molar activity (177 ± 5 GBq μmol -1 ), in high radiochemical purity (99%), and in a formulation suitable for animal injection. An in vitro cellular binding experiment demonstrated saturable binding of the radiotracer to A375 melanoma cells., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)