Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Nucl Med Biol. 2013 Jul;40(5):689-96. doi: 10.1016/j.nucmedbio.2013.02.013. Epub 2013 Apr 6.
Cardiac myosin is a potential molecular target for heart failure imaging since its changes can be used to assess the function of heart. In this study, two analogues of Omecamtiv Mecarbil, which is the first selective activator of cardiac myosin, were synthesized and radio-labeled with (18)F. Then the radio-compounds were evaluated as potential cardiac myosin imaging agent.
The labeling precursor and the nonradioactive compounds were synthesized and characterized by IR, (1)H NMR, (13)C NMR and MS analysis. By substituting bromo of precursors with (18)F, the radiolabeled compounds [(18)F]8 and [(18)F]10 were prepared and further evaluated for their in vitro physicochemical properties, stabilities, protein binding assay and ex vivo biodistribution.
Starting with [(18)F]F(-) Kryptofix 2.2.2./K2CO3 solution, the total reaction time for [(18)F]8 and [(18)F]10 was about 40 min respectively, with final high-performance liquid chromatography purification included. Typical decay-corrected radiochemical yield stayed at 12.47% ± 3.30% (n=8), the radiochemical purity, 98% or more. Their specific activity was estimated as 50 GBq/μmol. Both [(18)F]8 and [(18)F]10 could be stable after incubation in water at room temperature and in serum or binding buffer at 37 °C for 3h. Biodistribution in normal mice showed that both [(18)F]8 and [(18)F]10 have good heart uptake at 2 min post-injection time. Compound [(18)F]10 has better heart retention and higher heart to background ratios than those of [(18)F]8. In vitro protein binding assay demonstrates that [(18)F]10 may have high affinity with myosin from bovine heart.
[(18)F]8 and [(18)F]10 were synthesized with good radiochemical yield and high radiochemical purity (>98%). One of the compounds ([(18)F]10) has higher bovine heart myosin binding affinity and better heart/liver ratio. It will be further evaluated as a potent cardiac myosin imaging agent in normal and systolic heart failure model with positron emission tomography in the future.
肌球蛋白是心力衰竭成像的潜在分子靶标，因为其变化可用于评估心脏功能。在这项研究中，合成了两种 Omecamtiv Mecarbil 的类似物，它是心脏肌球蛋白的第一个选择性激活剂，并对其进行了（18）F 放射性标记。然后评估了放射性化合物作为潜在的心脏肌球蛋白成像剂。
通过用（18）F 取代前体的溴，制备了放射性标记化合物[（18）F]8和[（18）F]10，并进一步评估了它们的体外理化性质、稳定性、蛋白结合测定和离体生物分布。
以[（18）F]F（-）Kryptofix 2.2.2./K2CO3 溶液为起始原料，[（18）F]8和[（18）F]10 的总反应时间分别约为 40 分钟，最终包括高效液相色谱纯化。典型的放射性化学产率校正衰减值保持在 12.47%±3.30%（n=8），放射性化学纯度在 98%以上。它们的比活度估计为 50GBq/μmol。[（18）F]8和[（18）F]10 在室温下水和 37°C 下的血清或结合缓冲液中孵育 3h 后均可稳定。在正常小鼠中的生物分布显示，在注射后 2 分钟时，[（18）F]8 和[（18）F]10 都有良好的心脏摄取。化合物[（18）F]10 具有比[（18）F]8 更好的心脏保留和更高的心脏与背景比值。体外蛋白结合试验表明，[（18）F]10 可能与牛心肌球蛋白具有高亲和力。
[（18）F]8 和[（18）F]10 的放射性化学产率和放射性化学纯度（>98%）均较高。其中一种化合物[（18）F]10 具有更高的牛心肌球蛋白结合亲和力和更好的心脏/肝脏比值。将来，它将进一步用正电子发射断层扫描在正常和收缩性心力衰竭模型中作为一种有效的心脏肌球蛋白成像剂进行评估。
