含磺酰基硼酸帽的新型99mTc(Ⅲ)心肌显像剂的研究

Coronary artery disease (CAD) is the leading cause of premature death and permanent disability. Accurate early detection of CAD is highly desirable so that appropriate therapeutic regimens can be given before irreversible damage occurs in the patients with known or suspected CAD. Myocardial perfusion imaging (MPI) with radiotracers is a non-invasive technique showing the heart function and the areas of perfusion defects and remains an integral component in evaluation of CAD patients. An ideal perfusion radiotracer should have a high heart uptake with a stable myocardial retention, which linearly tracks the regional blood flow over a wide range flow rate (0 – 5 mL/min/g) and low liver uptake with high heart/background ratio. A significant drawback of 99mTc−Sestamibi and 99mTc-Tetrofosmin which are widely used for MPI in nuclear cardiology is its low first-pass extraction fraction and lack of linear relationship between its heart uptake and regional blood flow rates at >2.5 mL/min/g, so they are not ideal for imaging and cannot make the precise blood flow measurement.In contrast, 99mTc−Teboroxime has the highest first-pass extraction fraction and good uptake-flow linear relationship among all 99mTc radiotracers, but its early clinical experience was disappointing as its short myocardial retention and traditional SPECT with longer scan time. According of above we will optimize the 99mTc-Teboroxime with sulfonyl-containing boronate caps to make the heart retention longer with maintaining high first-pass extraction fraction for ideal MPI in nuclear cardiology.

冠心病是过早死亡和永久伤残的罪魁祸首。早期的精确诊断对于确定或疑似冠心病患者给予恰当的治疗方案有重要意义。核素心肌灌注显像是显示心肌功能和心肌灌注缺陷区域的无创检查，是CAD患者评价的一个手段。理想的灌注显像剂应该是心肌摄取高，心肌滞留稳定，心肌摄取与血流量在0-5mL/min/g线性范围良好，肝脏吸收低，心/背景比高。临床上广泛应用的99mTc-Sestamibi和99mTc-Tetrofosmin的显著缺点是心肌摄取低，心肌摄取和血流线性关系在大于2.5mL/min/g时缺失，因此显像仍不理想，也不能精确测量血流量。而99mTc-Teboroxime心肌摄取最高，线性范围良好，但心肌滞留太短，而传统的SPECT扫描时间长限制了其临床应用，因此，本课题拟研发基于磺酰基修饰的硼酸帽的新型99mTc-Teboroxime类化合物，以期保持高心肌首次摄取，延长心肌滞留时间，得到理想显像剂。

我国心血管疾病死亡率仍居疾病死亡构成的首位，心血管疾病的负担日渐加重，已成为重大的公共卫生问题，而且无病理征兆的心血管疾病也日益年轻化，精确诊断并提早精确治疗能有效预防和治疗心血管病患。核素心肌显像在心脏病患者对健康管理上有着重要的作用。SPECT 作为无创性核心脏学检查方法仍然是临床心血管疾病心肌功能评估不可缺少的诊断手段，是心血管疾病诊断的支柱。美国FDA批准的99mTc-Teboroxime ([99mTcCl(CDO) (CDOH)2B−Me]：CDOH2 = cyclohex-anedione dioxime)在所有99mTc显像剂中心肌首次摄取最高，线性关系良好，但是心肌清除太快，不能应用于临床，本课题主要设计其类似物，并成功制备通过平面成像生物分布初步筛选，发现99mTc-3Sboroxime， 99mTc-3SPboroxime， 99mTc-4Sboroxime相比99mTc-Teboroxime有更高的心脏吸收和心肌滞留时间。99mTc-3Sboroxime在2-min的AUC是99mTc-Teboroxime0-60min的2倍，因而最有潜力突破99mTc-Teboroxime的临床局限性，发展为新的优良心肌显像剂。