## 2 Results and Discussion  
### \({}^{11}\)C-Methylation of Unprotected Desmethyl Precursors  
We initially selected \(O\)-methylation of \(O\)-desmethyllocadenant (**8**) with [\({}^{11}\)C]MeI (Figure 2, route a) as a straightforward route for the preparation of [\({}^{11}\)C]lozadenant ([\({}^{11}\)C]**13**). Figure 1: Tozadenant-derived \({}^{18}\)F-labeled A\({}_{\text{2A}}\)R antagonists for PET imaging [14; 22]. Radiomethyllation precursor **8** was prepared in seven steps, starting from known 4-methoxy-7-morpholinobenz[\(d\)]thiazol-2-amine (**1**) [14] (Figure 3). To this end, **1** was first demethylated with boiling aqueous 48% hydrobromic acid, which afforded 2-amino-7-morpholinobenz[\(d\)]thiazol-4-ol (**2**) in excellent yield. Although subsequent Cs\({}_{2}\)CO\({}_{3}\)-supported \(O\)-alkylation of **2** with benzyl bromide directly furnished benzyl ether **5**, the desired product was obtained in low yields and always contaminated with a lipophilic impurity that proved difficult to remove by chromatography. In addition, sufficient chemoselectivity for benzylation of the phenolic \(OH\) over the amino group in **2** could be achieved neither at low temperatures nor by the use of stoichiometric reagent amounts, which necessitated chromatographic purification and resulted in low yields of the desired benzyl ether. As such, we instead opted to perform \(O\)-benzylation after appropriate protection of the amino group. Condensation of **2** with benzaldehyde to form the imine of the primary exocyclic amine while preserving the phenolic \(OH\) was unsuccessful. As an alternative, the amino group was protected by reaction of **2** with \(N\),\(N\)-dimethylformamide dimethyl acetal (DMF-DMA), which furnished the corresponding \(N\),\(N\)-dimethylformamide **3** in an over 90% yield. Subsequent Cs\({}_{2}\)CO\({}_{3}\)-supported \(O\)-benzylation of **3** at ambient temperature followed by \(N\)-deprotection of the resulting intermediate **4** with potassium hydroxide afforded benzyl ether **5** in a 77% yield over two steps. Compound **5** was then condensed with phenyl chloroformate using pyridine as a base to prepare phenyl carbamate **6** as a stable solid in almost quantitative yield. Next, the asymmetric \(N\),\(N^{\prime}\)-disubstituted urea **7** was synthesized by aminolysis of **6** under neutral conditions with DMSO as reaction solvent [25]. To this end, **6** was treated with a slight excess of 4-hydroxy-4-methylpiperidine at 50 \({}^{\circ}\)C, which rapidly generated **7** in an 83% yield. Finally, **7** was \(O\)-debenzylated by catalytic transfer hydrogenation (CTH) with Pd/C and a sixfold excess of ammonium formate as hydrogen donor [26] for ten min, which afforded precursor **8** in 74% yield. Unexpectedly, radiomethyllation of **8** with [\({}^{11}\)C]MeI using various reaction solvents, bases and reaction conditions failed and only unidentified products could be detected. In an attempt to enhance the nucleophilicity of the phenolic oxygen and the chemoselectivity of the methylation reaction [27], we also prepared the tetrabutylammonium (TBA) salt of precursor **8**. To this end, a suspension of **8** (1.2 equivalents) in MeOH was reacted with  
Figure 2: Investigated radiolabeling protocols for the preparation of [\({}^{11}\)C]lozadenant ([\({}^{11}\)C]**13**). Conditions: (a) [\({}^{11}\)C]MeI, base, solvent, t; (b) [\({}^{11}\)C]MeOTf, acetone or MeCN, rt; (c) [\({}^{11}\)C]MeI, 1 m NaOH\({}_{\text{aq}}\) (2 equiv), DMF, 60 \({}^{\circ}\)C; (d) [\({}^{11}\)C]MeI, 1 m NaOH\({}_{\text{aq}}\) (2 equiv), solvent, 60 \({}^{\circ}\)C.  
TBA hydroxide (1 equivalent) in MeOH followed by separation of unreacted precursor **8** by centrifugation, which afforded **8a** in 90% yield. However, radiomethylation of **8a** with [11C]methyl trifluoromentanesulfonate ([11C]methyl triflate) [28] in acetone or acetonitrile (Figure 2, route b) did not yield the desired product.