Dynamic PET Imaging of Elesclomol-Facilitated Copper Delivery in Ischemic Stroke Rats

Copper is an essential trace element that is required
at optimal
levels to support physiological functions in the cerebrovascular system.
Copper deficiency reduces vascular elasticity, potentially worsening
the ischemic stroke. Epidemiological evidence has linked higher copper
intake with reduced stroke risk. This study aimed to investigate Elesclomol
(ES) as a vector for delivering copper to the brain in models of ischemic
stroke. 64Cu-ES showed excellent serum stability in vitro. PET/CT imaging revealed that 64Cu-ES
exhibited longer brain retention compared to 64Cu-ATSM,
likely due to its higher lipophilicity. Ex vivo biodistribution
results were consistent with the imaging data. In normal SD rats, 64Cu-ES showed the highest uptake in the cingulate cortex,
followed by the striatum, cerebral cortex, hippocampus, thalamus,
and pons, with the lowest levels in the cerebellum and amygdala. In
ischemic SD rats, there was no significant difference in the 64Cu-ES uptake between the ischemic region and the contralateral
side up to 24 h post-administration. These results provide direct
evidence that ES can facilitate delivery of copper to the brain, supporting
its potential as a therapeutic candidate for copper supplementation
in ischemic stroke patients.

铜是一种必需的微量元素，需维持适宜水平以支持脑血管系统的生理功能。铜缺乏会降低血管弹性，可能加重缺血性脑卒中病情。流行病学证据表明，更高的铜摄入量与脑卒中风险降低相关。本研究旨在探究依来司罗（Elesclomol，ES）作为载体，将铜递送至缺血性脑卒中模型中的效果。64Cu-ES在体外展现出优异的血清稳定性。PET/CT成像结果显示，与64Cu-ATSM相比，64Cu-ES在脑中的滞留时间更长，这可能源于其更高的脂溶性。离体生物分布实验结果与成像数据一致。在正常SD大鼠（Sprague-Dawley大鼠）中，64Cu-ES在扣带回皮层中的摄取量最高，其次为纹状体、大脑皮层、海马体、丘脑和脑桥，小脑和杏仁核中的摄取量最低。在缺血性SD大鼠中，给药后24小时内，缺血区域与对侧区域的64Cu-ES摄取量无显著差异。上述结果直接证明ES可促进铜向脑中递送，支持其作为缺血性脑卒中患者补铜治疗候选药物的潜力。