Forschungszentrum Jülich GmbH, Institute of Neuroscience and Medicine, Nuclear Chemistry (INM-5), Wilhelm-Johnen-Str., 52428 Jülich, Germany.
Institute of Radiochemistry and Experimental Molecular Imaging, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
Molecules. 2024 Feb 29;29(5):1089. doi: 10.3390/molecules29051089.
Tozadenant (4-hydroxy--(4-methoxy-7-morpholinobenzo[]thiazol-2-yl)-4-methylpiperidine-1-carboxamide) is a highly selective adenosine A receptor (AR) antagonist and a promising lead structure for the development of AR-selective positron emission tomography (PET) probes. Although several F-labelled tozadenant derivatives showed favorable in vitro properties, recent in vivo PET studies observed poor brain penetration and lower specific binding than anticipated from the in vitro data. While these findings might be attributable to the structural modification associated with F-labelling, they could also reflect inherent properties of the parent compound. However, PET studies with radioisotopologues of tozadenant to evaluate its cerebral pharmacokinetics and brain distribution are still lacking. In the present work, we applied -Boc--desmethyltozadenant as a suitable precursor for the preparation of [-methyl-C]tozadenant ([C]tozadenant) by -methylation with [C]methyl iodide followed by acidic deprotection. This approach afforded [C]tozadenant in radiochemical yields of 18 ± 2%, with molar activities of 50-60 GBq/µmol (1300-1600 mCi/µmol) and radiochemical purities of 95 ± 3%. In addition, in vitro autoradiography in pig and rat brain slices demonstrated the expected striatal accumulation pattern and confirmed the AR specificity of the radioligand, making it a promising tool for in vivo PET studies on the cerebral pharmacokinetics and brain distribution of tozadenant.
托扎丹南（4-羟基-（4-甲氧基-7-吗啉基苯并[2,3-d]噻唑-2-基）-4-甲基哌啶-1-甲酰胺）是一种高选择性的腺苷 A 受体（AR）拮抗剂，也是开发 AR 选择性正电子发射断层扫描（PET）探针的有前途的先导结构。尽管几种 F 标记的托扎丹南衍生物表现出良好的体外特性，但最近的体内 PET 研究观察到与体外数据预期相比，脑穿透性差且特异性结合降低。虽然这些发现可能归因于与 F 标记相关的结构修饰，但它们也可能反映出母体化合物的固有特性。然而，仍缺乏使用托扎丹南的放射性同位素类似物进行的 PET 研究，以评估其脑药代动力学和脑分布。在本工作中，我们应用 -Boc--去甲基托扎丹南作为合适的前体，通过用[C]甲基碘进行 -甲基化，然后进行酸性脱保护，制备[-甲基-C]托扎丹南（[C]托扎丹南）。这种方法以 18±2%的放射化学产率提供[C]托扎丹南，摩尔活度为 50-60GBq/µmol（1300-1600mCi/µmol），放射化学纯度为 95±3%。此外，在猪和大鼠脑切片的体外放射自显影中，证实了放射性配体预期的纹状体积累模式，并证实了 AR 特异性，使其成为研究托扎丹南脑药代动力学和脑分布的体内 PET 研究的有前途的工具。
