It is currently hypothesized that adenosine is involved in the induction of sleep after prolonged wakefulness. This effect is partially reversed by the application of caffeine, which is a nonselective blocker of adenosine receptors. Here, we report that the most abundant and highly concentrated A₁subtype of cerebral adenosine receptors is upregulated after 24 h of sleep deprivation. We used the highly selective A₁adenosine receptor (A₁AR) radioligand [¹⁸F]CPFPX ([¹⁸F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine) and quantitative positron emission tomography to assess cerebral A₁ARs before and after sleep deprivation in 12 healthy volunteers and a control group (n= 10) with regular sleep. In sleep deprived subjects, we found an increase of the apparent equilibrium total distribution volume in a region-specific pattern in all examined brain regions with a maximum increase in the orbitofrontal cortex (15.3%;p= 0.014). There were no changes in the control group with regular sleep. This is the first molecular imaging study that providesin vivoevidence for an A₁AR upregulation in cortical and subcortical brain regions after prolonged wakefulness, indicating that A₁AR expression is contributing to the homeostatic sleep regulation.

Iodonium ylide precursors of electron rich arenes, i.e. the NET and SERT ligands 4-((3- and 4-fluorophenoxy)phenylmethyl)piperidine, served as model compounds for the direct substitution with n.c.a. [ ¹⁸ F]fluoride.

The ¹⁸F-labeled aromatic amino acid 6-fluoro-3,4-dihydroxy-l-phenylalanine (6-¹⁸F-fluoro-l-DOPA) is widely used as a radiopharmaceutical in neurologic and oncologic PET. In this study, a novel approach to the preparation of carrier-added (CA) 6-¹⁸F-fluoro-l-DOPA in 3 radiosynthesis steps was developed and evaluated; in this approach, direct nucleophilic ¹⁸F fluorination of a protected amino acid derivative was used. The method currently used for the routine preparation of 6-¹⁸F-fluoro-l-DOPA by electrophilic labeling is limited to the production of small amounts of activity at high costs. Alternative syntheses based on the advantage of large-scale production of nucleophilic ¹⁸F-fluoride, however, either have resulted in insufficient enantiomeric purity or are difficult to automate because of the complexity of the necessary multiple steps. Methods: An isotopic exchange reaction on the precursor (2S,5S)-tert-butyl-5-(4-benzyloxy-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate was used. The formyl group served as the activating group in the ¹⁸F-for-¹⁹F exchange with tetrabutylammonium bicarbonate for anion activation in N,N-dimethylformamide. The intermediate was converted to a hydroxy group by Baeyer–Villiger oxidation with meta-chloroperbenzoic acid. After final deprotection with hydrobromic acid, CA 6-¹⁸F-fluoro-l-DOPA was isolated by high-performance liquid chromatography. Results: The precursor was obtained by an 11-step organic synthesis. The optimized isotopic ¹⁸F exchange proceeded with a radiochemical yield of about 50%. The complete preparation and isolation of CA 6-¹⁸F-fluoro-l-DOPA thus far are possible with a radiochemical yield of about 22%, within a synthesis time of 105 min, and at a much higher specific activity than with the electrophilic method. The enantiomeric excess of the desired l-isomer was greater than 96%.Conclusion: The pathway to 6-¹⁸F-fluoro-l-DOPA by isotopic exchange not only is more efficient but also is suited to automation as a “one-pot” procedure.