Expanding PET-applications in life sciences with positron-emitters beyond fluorine-18

Positron emission tomography (PET) has become an indispensable diagnostic tool in modern nuclear medical diagnostics. Its outstanding molecular imaging features allow repetitive studies on one individual and with high sensitivity, though no interference. Rather few positron emitters with near favourable physical properties, i.e. carbon-11 and fluorine-18, furnished most studies in the beginning, preferably if covalently bound as isotopic label of small molecules. With the advancement of PET-devices the scope of in vivo research in life sciences and especially that of medical applications expanded, and other than “standard” PET-nuclides received increasing significance, like the radiometals copper-64 and gallium-68. Especially during the last decades, positron emitters of other chemical elements have gotten into the focus of interest, concomitant with the technical advancements in imaging and radionuclide production. With known nuclear imaging properties and main production methods of emerging positron emitters their usefulness for medical application is promising and even proven for several ones already. Unfortunate decay properties could be corrected for, and β+-emitters, especially with a longer half-life, provided new possibilities for application where slower processes are of importance.Further on, (bio)chemical features of positron emitters of other elements, among there many metals, not only expanded the field of classical clinical investigations, but also opened up new fields of application. Appropriately labelled peptides, proteins and nanoparticles lend itself as newer probes for PET-imaging, e.g. in theragnostic or PET/MR hybrid imaging. Furthermore, the potential of non-destructive in-vivo imaging with positron emission tomography directs the view on further areas of life sciences. Thus, exploiting the excellent methodology for basic research on molecular biochemical functions and processes is increasingly encouraged as well in areas outside of health, such as plant and environmental sciences

4-[18F]Fluorophenylpiperazines by Improved Hartwig-Buchwald N-Arylation of 4-[18F]fluoroiodobenzene, Formed via Hypervalent λ3-Iodane Precursors: Application to Build-Up of the Dopamine D4 Ligand [18F]FAUC 316

Substituted phenylpiperazines are often neuropharmacologically active compounds and in many cases are essential pharmacophores of neuroligands for different receptors such as D2-like dopaminergic, serotoninergic and other receptors. Nucleophilic, no-carrier-added (n.c.a.) 18F-labelling of these ligands in an aromatic position is desirable for studying receptors with in vivo molecular imaging. 1-(4-[18F]Fluorophenyl)piperazine was synthesized in two reaction steps starting by 18F-labelling of a iodobenzene-iodonium precursor, followed by Pd-catalyzed N-arylation of the intermediate 4-[18F]fluoro-iodobenzene. Different palladium catalysts and solvents were tested with particular attention to the polar solvents dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Weak inorganic bases like potassium phosphate or cesium carbonate seem to be essential for the arylation step and lead to conversation rates above 70% in DMF which is comparable to those in typically used toluene. In DMSO even quantitative conversation was observed. Overall radiochemical yields of up to 40% and 60% in DMF and DMSO, respectively, were reached depending on the labelling yield of the first step. The fluorophenylpiperazine obtained was coupled in a third reaction step with 2-formyl-1H-indole-5-carbonitrile to yield the highly selective dopamine D4 ligand [18F]FAUC 316

Do we say what we mean and mean what we say?

Over the last 7 decades the use of radionuclides in the natural andlife sciences has been crucial in enabling groundbreaking discoveriesin basic research and its application to the understanding, diagnosingand treatment of human disease. Numerous innovations in nuclearchemistry/physics, radiochemistry and instrumentation (from nuclearreactors and cyclotrons to new imaging devices) have enabled the ap-plication of radiolabeled molecules in biochemistry, physiology, phar-macology, clinical diagnosis and therapy. These developments haverelied on the continual evolution of cross-disciplinary interactions be-tween researchfields, resulting in a new generation of researchersfrom disparate scientific backgrounds working very successfullytogether.The importance of a unified language betweenfields has long beenrecognized and resulted in the establishment of SI units and IUPAC no-menclature to enableunambiguous scientific communication. However,despite this, the meaning of scientific terms has sometimes beeninterpreted in slightly different ways within different disciplines. Overrecent years in thefield of radiopharmaceutical sciences we havewitnessed an increased incidence of ambiguous scientificlanguage.Many examples of the incorrect usage of established terms and conven-tions and the appearance of new‘self-invented’terms can now be foundin theliterature and at scientific meetings.Thedeparture from the useofa common language is contributing to misunderstanding and confusionwithin our scientific community, and in our communication with otherscientificdiscipline

New strategy of a two-step radiosynthesis of [F-18]fluoropyridine-based maleimide-containing prosthetic groups for labelling of peptides and proteins

Objectives The use of thiol-reactive groups allows the introduction of fluorine-18 in a peptide or protein with cysteine residues, and different radiofluorinated maleimide-containing prosthetic groups have been described in the literature. All compounds were, however, prepared by a two- or three-step synthesis with an overall reaction time of at least 70 minutes. The aim of this work was to improve the radiosynthesis of maleimide-containing compounds with reduced reaction steps by using a new synthetic route via protection of the maleimide function. This was first done here with the example of 1-[3-(2-[18F]fluoropyridin-3-oxy)propyl]pyrrol-2,5-dione ([18F]FPyME) which is usually prepared in three steps [1]. Methods The first step for the preparation of the precursor was a Williamson reaction to form the ether from 3-hydroxy-2-nitropyridine with 1,3-dibromopropane. In a parallel process maleimide was protected with 2,5-dimethylfurane via a Diels-Alder-reaction. These two products were combined by N-alkylation to form the precursor. The radiosynthesis includes the introduction of fluorine-18 by nucleophilic substitution of the nitro group followed by deprotection of the maleimide function (see fig. 1). The reaction steps were optimized with regard to temperature, time and solvents. Results The optimal conditions for the n.c.a. radiofluorination were identified at a temperature of 80 °C in DMSO and a reaction time of 5 minutes, resulting in a radiochemical yield of about 29 ± 3 %. At higher temperatures the deprotection of the precursor and the labelled compound come to the fore and thereby the decomposition of the unprotected maleimide occurs due to the basic reaction conditions. The deprotection step was quantitatively carried out within 15 minutes. [18F]FPyME was isolated by HPLC to provide the pure prosthetic group which was directly used for effective peptide labelling. The overall synthesis time was about 60 minutes and the overall radiochemical yield was about 20 %. Conclusions The described synthetic route provides the possibility to gain a variety of further [18F]fluoropyridine-based maleimide-containing compounds in two steps only. In addition, this method offers to be performed as one-pot synthesis. Acknowledgements References [1] de Bruin B. et al. (2006) Bioconjugate Chem., 16, 406-420