The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D₂-receptor ligands is reported. The SiFA-technology simplifies the introduction of fluorine-18 into target specific biomolecules for Positron-Emission-Tomography (PET). However, one of the remaining challenges, especially for small molecules such as receptor-ligands, is the bulkiness of the SiFA-moiety. We therefore synthesized four Fallypride SiFA-conjugates derivatized either directly at the benzoic acid ring system (SiFA-DMFP, SiFA-FP, SiFA-DDMFP) or at the butyl-side chain (SiFA-M-FP) and tested their receptor affinities. We found D₂-receptor affinities for all compounds in the nanomolar range (K_i(SiFA-DMFP) = 13.6 nM, K_i(SiFA-FP) = 33.0 nM, K_{i(SiFA-DDMFP)} = 62.7 nM and K_i(SiFA-M-FP) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with [¹⁸F]fluoride/TBAHCO₃ in acetonitrile. After a reversed phased cartridge purification the desired products could be isolated as an injectable solution after only 10 min synthesis time with radiochemical yields (RCY) of more than 40% in the case of SiFA-DMFP resulting in specific activities >41 GBq/µmol (>1,100 Ci/mmol). Furthermore, the radiolabeled products were shown to be stable in the injectable solutions, as well as in human plasma, for at least 90 min.

Levosimendan is used in severe chronic cardiac insufficiency, also within the peri-operative setting. Real-life pharmacokinetic data in surgical patients is lacking, making therapeutic drug monitoring (TDM) of levosimendan, its pharmacologically active metabolite OR-1896, and its intermediate OR-1855 important. A simultaneous highly sensitive quantification of levosimendan and its metabolites in small-volume samples has not yet been described. Here, levosimendan (LLOQ 0.450 nM), OR-1896, and OR-1855 (LLOQ both 1.0 nM) were successfully quantified by LC-ESI-MS/MS after liquid-liquid extraction in 300 µL of blood. A short C8 column under reversed-phase conditions enabled simultaneous and fast quantification of levosimendan in the negative and the metabolites in the positive ionization mode in a single run within 2 min. Interestingly and unexpectedly, constitutional isomers of levosimendan metabolites with identical mass transitions and similar retention times were observed in surgical patients’ samples, which we identified as the metamizole metabolites 4-aminoantipyrine and 4-acetamidoantipyrine. A longer C8 column and a modified mobile phase enabled selective quantification of all analytes in a single run within 7 min. We developed, validated, and applied highly sensitive LC-ESI-MS/MS methods for simultaneous quantification of levosimendan and its metabolites, enabling efficient TDM of cardiac surgery patients even with additional metamizole administration.

The back cover picture shows affinity profiling at monoamine transporters following the concept of MS Binding Assays. Monitoring (1R,3S)-indatraline as a single nonlabeled reporter ligand for the three targets DAT (orange), NET (green), and SERT (purple) by LC-MS/MS enabled determination of corresponding inhibitors' affinities. The results obtained demonstrate the power of MS Binding Assays as an efficient alternative to radioligand binding assays. For further details, see the Full Paper by Klaus T. Wanner et al. on p. 1027 ff.

The cover picture shows a label-free screening technique to characterize target–ligand interactions. In the foreground, a triple quadrupole mass spectrometer positioned in a flowering meadow illustrates the environmentally friendly opportunity to realize binding assays based on mass spectrometric quantification of a nonlabeled marker compound for a desired target. By peeling back the illustration of this concept—referred to as MS binding assays—the cover picture visualizes the implementation of this approach to the serotonin transporter (SERT). The study describes the efforts to address binding of nonlabeled fluoxetine enantiomers to SERT, as well as the promising results generated by the application of this MS binding assay strategy. For more details, see the Full Paper by Klaus T. Wanner et al. on p. 1900 ff.