## 1 Introduction  
The nucleoside adenosine is a pleiotropic signaling molecule that mediates its cellular effects by activation of four different adenosine receptor (AR) subtypes (A\({}_{1}\)R, A\({}_{2\text{A}}\)R, A\({}_{2\text{B}}\)R and A\({}_{3}\)R) [1]. The predominant AR subtypes in the central nervous system are A\({}_{1}\)R and A\({}_{2\text{A}}\)R, which participate in the regulation of many physiological processes like wakefulness, cognition and motor function [2; 3; 4]. While A\({}_{1}\)Rs are widely expressed throughout the whole brain, A\({}_{2\text{A}}\)Rs show a more restricted expression pattern, with high levels in the striatum and much lower levels in extra- striatal brain regions [1; 5; 6; 7; 8]. In addition, many neuroinflammatory and neurodegenerative conditions have been shown to be associated with changes in the distribution and/or function of A\({}_{2\text{A}}\)Rs, making them attractive therapeutic targets for a wide spectrum of neurological diseases [8; 9; 10]. For example, inhibition of the striatopallidal motor pathway with selective A\({}_{2\text{A}}\)R antagonists like tozadenant (4-hydroxy-N-(4-methoxy-7-morpholino-4-yl-1,3-benzo[d]thiazol-2-yl])-4-methylpiperidine-1-carboxamide) has been pursued as a non-dopaminergic treatment option for Parkinson's disease (PD) [11; 12]. Although tozadenant effectively improved PD symptomatology with virtually no off-targeteffects, reports of hematological toxicity during long-term treatment necessitated early termination of phase 3 clinical trials [13]. Nevertheless, its high affinity (K\({}_{\text{i}}\) = 3.9-4.9 nM for human A\({}_{\text{2A}}\)R) [8; 14], unique target selectivity [15] and high in vivo stability [16; 17] position tozadenant as a promising lead structure for the development of positron emission tomography (PET) probes, which could be used to visualize and quantify cerebral A\({}_{\text{2A}}\)Rs in patients with PD or other neurological diseases [9; 18]. Thus, taking into account reported densities of A\({}_{\text{2A}}\)Rs in the human striatum (B\({}_{\text{max}}\) = 259-870 fmol/mg protein [8; 19; 20]), the estimated (in vitro) binding potential (B\({}_{\text{max}}\)/K\({}_{\text{i}}\)) for tozadenant (>5) indicates that radio-labeled analogs with comparable or superior affinity could be suitable for quantitative comparisons with PET imaging [21]. Accordingly, a number of \({}^{18}\)F-labeled tozadenant derivates have been developed (Figure 1) and evaluated by in vitro autoradiography, which generally demonstrated an excellent A\({}_{\text{2A}}\)R specificity of these radiologists [14; 22]. On the other hand, preclinical in vivo evaluation of \({}^{18}\)F-labeled tozadenant derivates performed so far revealed a rather low brain penetration and considerably lower specific binding than anticipated from in vitro studies [22; 23]. Given that the cerebral pharmacokinetics and brain distribution of tozadenant itself have never been examined, these findings could reflect undesirable in vivo properties of the benzothiazole scaffold and/or negative effects of the structural modifications associated with \({}^{18}\)F-labeling. For example, while the quotient of receptor density and affinity (i.e., B\({}_{\text{max}}\)/K\({}_{\text{i}}\)) provides an upper limit for striatal accumulation, slow blood-brain barrier (BBB) penetration, active export across the BBB or other pharmacokinetic features of the benzothiazole scaffold itself (e.g., unsuitable lipophilicity) could significantly reduce the in vivo availability of tozadenant or derived radiologists in the brain [8]. Thus, although existing evidence indicates that the extent of brain entry during continued treatment with tozadenant was sufficient for clinical efficiency, neither the kinetics of brain penetration nor the lipophilicity or interaction with drug excretion pumps like P-gp have been studied to date and multiple probabilistic scores indicative of BBB penetration were indeed rather low [24].