适用于SPECT心肌血流绝对定量的心肌灌注显像创新药物的实验研究

SPECT myocardial perfusion imaging is the most commonly used technique in the diagnosis of myocardial ischemia. However, there is a lack of optimal perfusion imaging radiotracers. The low first-pass extraction fraction of 99mTc-MIBI and 99mTc-tetrofosmin, which is unable to linearly track the regional blood flow over a wide range flow rate, limits the use in absolute quantitative analysis in the clinics. The proposed study intends to develop new myocardial perfusion imaging agents with dioxime boronate structure. In this new structure, cyclohexanedione dioxime boronate is used to maintain high and fast myocardial uptake and sulfonyl phenyl/pyridine caps are introduced to extend myocardial retention times and reduce the liposolubility leading to lower uptake in liver and lung. The ideal structure with better biological and metabolic kinetics will be screened by biodistribution and microSPECT imaging studies in rats. Then, myocardial ischemia mini-swine models and healthy controls will undergo dynamic SPECT perfusion imaging to establish absolute quantification of myocardial blood flow, which is based on full physical corrections and validated by “golden standard” fluorescent microsphere experiments. This project combines new radiotracers with new SPECT myocardial blood flow quantification technique, which assist revascularization strategy decision and microcirculation function assessment and has important clinical significance.

SPECT心肌灌注显像是检测心肌缺血常用的影像学技术，但仍缺乏理想的显像药物。99mTc-MIBI和99mTc-tetrofosmin心肌首次提取率低，使心肌摄取与心肌血流量无法在较宽范围内保持线性相关，用于心肌血流定量分析受到限制。本项目将研制新型二肟硼酸类心肌灌注显像药物，以环己二酮二肟硼酸结构维持心肌的快速、高度摄取，引入全新的磺酰基苯基或吡啶基“硼酸帽”结构，延长心肌滞留时间，适当降低脂溶性以减少肝肺摄取。以大鼠生物分布和MicroSPECT实验，筛选出生物学和代谢动力学特征较为理想的药物结构。对健康和心肌缺血小型猪进行动态SPECT显像，建立基于完整物理校正的心肌血流绝对定量新技术，并以“金标准”荧光微球实验验证。本项目将新型显像药物和SPECT心肌血流绝对定量新技术有机结合，适应冠心病再血管化治疗决策和心肌微循环障碍评价对影像学新技术的迫切要求，具有重要的临床意义。

SPECT心肌灌注显像是冠心病心肌缺血诊断最重要的影像学技术之一，目前存在的主要问题是由于显像药物的心肌首次提取率较低，难以满足心肌血流定量的要求。本项目针对上述问题，开展了新型99mTc标记硼酸衍生物结构心肌灌注显像药物的研究。从以苯基和吡啶基“硼酸帽”为结构特征的四种前体化合物中，通过放射化学纯度测定、体内生物学分布和药代动力学研究、大鼠MicroSPECT显像实验、健康和急性心肌缺血小型猪SPECT显像实验，筛选出一种性能最佳的心肌灌注显像药物99mTc-3SPboroxime。该药物具有心肌首次提取率较高、心肌滞留时间较长、肝脏摄取相对较低的优势。同时，采用动态显像和物理校正等新技术，建立了适用于99mTc-3SPboroxime的心肌血流定量分析方法。研究表明： 99mTc-3SPboroxime是一种较为理想的心肌灌注显像药物，具有自主知识产权，有较好的临床转化前景。