Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK.
School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London, SE1 7EH, UK.
Dalton Trans. 2021 Oct 26;50(41):14695-14705. doi: 10.1039/d1dt02224e.
Radiolabelled lipophilic cations can be used to non-invasively report on mitochondrial dysfunction in diseases such as cardiovascular disease, cardiotoxicity and cancer. Several such lipophilic cations are currently used clinically to map myocardial perfusion using SPECT imaging. Since PET offers significant advantages over SPECT in terms of sensitivity, resolution and the capacity for dynamic imaging to allow pharmacokinetic modelling, we have synthesised and radiolabelled a series of NODAGA-based radiotracers, with triarylphosphonium-functionalisation, with gallium-68 to develop PET-compatible cationic complexes. To evaluate their capacity to report upon mitochondrial membrane potential, we assessed their pharmacokinetic profiles in isolated perfused rat hearts before and after mitochondrial depolarisation with the ionophore CCCP. All three tracers radiolabel with over 96% RCY, with log values above -0.4 observed for the most lipophilic example of this family of radiotracers. The candidate tracer exhibited non-preferential uptake in healthy cardiac tissue over CCCP-infused cardiac tissue. While this approach does show promise, the lipophilicity of this family of probes needs improving in order for them to be effective cardiac imaging agents.
放射性标记的亲脂性阳离子可用于非侵入性地报告心血管疾病、心脏毒性和癌症等疾病中的线粒体功能障碍。目前有几种这样的亲脂性阳离子被临床用于使用 SPECT 成像来绘制心肌灌注图。由于 PET 在灵敏度、分辨率以及进行动态成像以允许药代动力学建模方面优于 SPECT，我们已经合成并放射性标记了一系列基于 NODAGA 的放射性示踪剂，用三芳基膦官能化，并用镓-68 开发了适用于 PET 的阳离子配合物。为了评估它们报告线粒体膜电位的能力，我们在使用离子载体 CCCP 使线粒体去极化前后，评估了它们在分离灌注的大鼠心脏中的药代动力学特征。所有三种示踪剂的放射性标记率均超过 96%，对于该放射性示踪剂家族中最亲脂的化合物，观察到 logD 值超过-0.4。候选示踪剂在健康心脏组织中的摄取没有优先于 CCCP 灌注的心脏组织。虽然这种方法确实有希望，但需要提高这类探针的亲脂性，以使它们成为有效的心脏成像剂。
