Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Germany.
Department of Research and Development, ROTOP Pharmaka Ltd., Dresden, Germany.
Eur J Nucl Med Mol Imaging. 2021 Aug;48(9):2727-2736. doi: 10.1007/s00259-020-05164-4. Epub 2021 Feb 2.
The adenosine A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A receptor radiotracer and report herein the preclinical evaluation of [F]FLUDA, a deuterated isotopologue of [F]FESCH.
[F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats.
[F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72-180 GBq/μmol. Autoradiography proved A receptor-specific accumulation of [F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [F]FLUDA compared to that of [F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [F]FLUDA towards striatal A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [F]FLUDA.
The new radiotracer [F]FLUDA is suitable to detect the availability of the A receptor in the brain with high target specificity. It is regarded ready for human application.
腺苷 A 受体已成为多种疾病的治疗靶点，因此，对 A 受体表达或占据的非侵入性成像有可能有助于诊断和药物开发。我们旨在开发一种代谢稳定的 A 受体放射性示踪剂，并在此报告 [F]FLUDA 的临床前评估，这是 [F]FESCH 的氘代同位素。
通过两步一锅法合成 [F]FLUDA，并通过放射性自显影研究以及在基线和阻断条件下在小鼠和仔猪体内进行代谢和动态 PET/MRI 研究进行体外评估。在大鼠中进行了单次剂量毒性研究。
[F]FLUDA 的放射化学产率为 19%，摩尔活度为 72-180GBq/μmol。放射自显影证明 [F]FLUDA 在小鼠和猪脑纹状体中具有 A 受体特异性积聚。在小鼠体内的评估表明，与 [F]FESCH 相比，[F]FLUDA 的稳定性得到了改善，导致没有穿透大脑的放射性代谢物。此外，在仔猪中检测到的放射性代谢物预计具有低穿透大脑的趋势。PET/MRI 研究证实，[F]FLUDA 与纹状体 A 受体具有高特异性结合，在小鼠中最大特异性与非特异性结合比值为 8.3。毒性研究表明，FLUDA 高达 30μg/kg 时没有不良反应，这是在使用 [F]FLUDA 进行人类 PET 研究中应用的剂量的 4000 倍。
新型放射性示踪剂 [F]FLUDA 适合用于检测大脑中 A 受体的可用性，具有高靶特异性。它被认为可以立即用于人体应用。
