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Isotopic labeling is at the core of health and life science applications such as nuclear imaging, metabolomics and plays a central role in drug development. The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Based on a rationally driven approach, this study presents an innovative solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy. The technology conceptualizes an opportunity in the field of isotope labeling. 15 N-labeling of pyridines and other relevant heterocycles such as pyrimidines and isoquinolines showcases on a large set of derivatives, including pharmaceuticals. Finally, we explore a nitrogen-to-carbon exchange strategy in order to access 13 C-labeled phenyl derivatives and deuterium labeling of mono-substituted benzene from pyridine- 2 H 5 . These results open alternative avenues for multiple isotope labeling on aromatic cores. The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Here the authors present a solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy.

This guideline on molar activity (Am) and specific activity (As) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of Am and As, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of Am and As in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common Am pitfalls and remedies are described. Finally, some aspects of Am in relation the emergence of a new generation of highly sensitive PET scanners will be discussed.

Aim: The receptor for advanced glycation end products (RAGE) is a viable target for early Alzheimer’s disease (AD) diagnosis using positron emission tomography (PET) as RAGE overexpression precedes Aβ plaque formation. The development of a carbon-11 analog of FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide, [11C]FPS-ZM1), possessing nanomolar affinity for RAGE, may enable the imaging of RAGE for early AD detection. Methodology & results: Herein we report an optimized [11C]CO2-to-[11C]CO chemical conversion for the synthesis of [11C]FPS-ZM1 and in vitro brain autoradiography. The [11C]CO2-to-[11C]CO conversion via 11C-silanecarboxylate derivatives was achieved with a 57% yield within 30 s from end of [11C]CO2 delivery. [11C]FPS-ZM1 was obtained with a decay-corrected isolated radiochemical yield of 9.5%. Conclusion: [11C]FPS-ZM1 distribution in brain tissues of wild-type versus transgenic AD model mice showed no statistically significant difference and high nondisplaceable binding.

This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.

This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.

Background Formamides are common motifs of biologically-active compounds (e.g. formylated peptides) and are frequently employed as intermediates to yield a number of other functional groups. A rapid, simple and reliable route to [ carbonyl - 11 C]formamides would enable access to this important class of compounds as in vivo PET imaging agents. Results A novel radiolabelling strategy for the synthesis of carbon-11 radiolabelled formamides ([ 11 C]formamides) is presented. The reaction proceeded with the conversion of a primary amine to the corresponding [ 11 C]isocyanate using cyclotron-produced [ 11 C]CO 2 , a phosphazene base (2- tert -butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, BEMP) and phosphoryl chloride (POCl 3 ). The [ 11 C]isocyanate was subsequently reduced to [ 11 C]formamide using sodium borohydride (NaBH 4 ). [ 11 C]Benzyl formamide was obtained with a radiochemical yield (RCY) of 80% in 15 min from end of cyclotron target bombardment and with an activity yield of 12%. This novel method was applied to the radiolabeling of aromatic and aliphatic formamides and the chemotactic amino acid [ 11 C]formyl methionine (RCY = 48%). Conclusions This study demonstrates the feasibility of 11 C-formylation of primary amines with the primary synthon [ 11 C]CO 2 . The reactivity is proportional to the nucleophilicity of the precursor amine. This novel method can be used for the production of biomolecules containing a radiolabelled formyl group.

BackgroundThe Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development.Main bodyThis selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals.ConclusionTrends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Background [ 18 F]BF 4 − , the first 18 F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [ 18 F]BF 4 − with higher SA. Methods A new radiosynthesis of [ 18 F]BF 4 − was developed, involving reaction of [ 18 F]F − with boron trifluoride diethyl etherate under anhydrous conditions, guided by 11 B and 19 F NMR studies of equilibria involving BF 4 − and BF 3 . The SA of the product was determined by ion chromatography. The IC 50 of [ 19 F]BF 4 − as an inhibitor of [ 18 F]BF 4 − uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [ 19 F]BF 4 − dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting. Results An IC 50 of 4.8 μΜ was found in vitro indicating a significant risk of in vivo NIS saturation at SA achieved by the isotopic exchange labelling method. In vivo thyroid and salivary gland uptake decreased significantly with [ 19 F]BF 4 − doses above ca. 10 μg/kg. The new radiosynthesis gave high radiochemical purity (>99 %) and moderate yield (15 %) and improved SA (>5 GBq/μmol) from a starting activity of only 1.5 GBq. Conclusions [ 18 F]BF 4 − produced at previously reported levels of SA (1 GBq/μmol) can lead to reduced uptake in NIS-expressing tissues in mice. This is much less likely in humans. The synthetic approach described provides an alternative for production of [ 18 F]BF 4 − at higher SA with sufficient yield and without need for unusually high starting activity of [ 18 F]fluoride, removing the risk of NIS saturation in vivo even in mice. Trial registration ISRCTN75827286 .

The preparation of an Investigational Medicinal Product Dossier (IMPD) for a radiopharmaceutical to be used in a clinical trial is a challenging proposition for radiopharmaceutical scientists working in small-scale radiopharmacies. In addition to the vast quantity of information to be assembled, the structure of a standard IMPD is not well suited to the special characteristics of radiopharmaceuticals. This guideline aims to take radiopharmaceutical scientists through the practicalities of preparing an IMPD, in particular giving advice where the standard format is not suitable. Examples of generic IMPDs for three classes of radiopharmaceuticals are given: a small molecule, a kit-based diagnostic test and a therapeutic radiopharmaceutical.