新型99mTc(III) 复合体作为SPECT心肌灌注显像剂的研究

Evaluation of myocardial perfusion with SPECT under stress and rest conditions has been a corner stone in the management patients with known or suspected coronary artery disease (CAD). Despite recent development of stress echocardiography and coronary CT angiography, myocardial perfusion imaging (MPI) with SPECT radiotracers remains a mainstay of non-invasive evaluations of patients with known or suspected CAD in nuclear cardiology practice. Over the past 10 years, the overwhelming success of SPECT MPI is, in large part, due to widespread clinical applications of 99mTc-Sestamibi and 99mTc-Tetrofosmin. It is expected that SPECT MPI will continue to play a major role for nuclear cardiology for many years ahead. Successful development of high quality radiotracers remains a key for the future of nuclear cardiology. Since early 1980s, intensive efforts have focused on cationic 99mTc complexes as perfusion radiotracers for MPI. Despite their widespread clinical applications, both 99mTc-Sestamibi and 99mTc-Tetrofosmin do not meet the requirements of an ideal perfusion radiotracer, in large part, due to their high liver uptake and relatively low first pass extraction fraction. 99mTc-Teboroxime [99mTcCl(CDO)(CDOH)2B-Me] is a member of the BATO-type (BATO=boronic acid adduct of technetium dioxime) radiotracers, and has the highest first-pass extraction fraction among all myocardial perfusion radiotracers and a linear relationship between its heart uptake and myocardial blood flow over a wide range (0–4.5mL/min/g). Despite this advantage, the overall clinical experience was disappointing because of its short myocardial residence time. With tremendous improvements in SPECT cameras over past several years, the leaders in the field of nuclear cardiology have been repeatedly calling for newer and better perfusion radiotracers with improved biodistribution and/or extraction properties. In this project 8 novel 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R=P1, P2, P4, P6, P8, P12, P16, P20, P24) will be prepared. Thiolate-S forms a stronger bonding with Tc(III) than Cl will stabilize the Tc(III) core and prevent rapid hydrolysis of 99mTc radiotracers, thereby increasing the radiotracer myocardial retention. Polyether (PEG) groups are used to reduce liver uptake and increase myocardial retention of 99mTc radiotracers. Their heart uptake and T/B ratios will be optimized by changing the chain length of the PEG groups. The SD rats will be used to evaluate the heart uptake and biodistribution of 8 complexes. Dynamic planar imaging of the SD rats will be used for assessment of radiotracer uptake and its clearance kinetics from the heart and normal organs. The objective of this project is to select an optimal 99mTc radiotracer that has high heart uptake and high first pass extraction with longer myocardial retention and minimize liver uptake than those of 99mTc-Teboroxime for future evaluations in large animals and to develop a clinically useful 99mTc radiotracer.

现今临床应用最广泛的心肌灌注显像剂是99mTc-Sestamibi和99mTc-Tetrofosmin，显像特性不够理想，心肌摄取及首次提取低，肝脏摄取高。99mTc-Teboroxime 在现有显像剂中心肌摄取及首次提取最高，且心肌摄取和心肌血流在很大范围具有良好线性关系，但心脏滞留时间太短，无法满足心肌显像。本项目拟对99mTc-Teboroxime进行修饰，制备8种新型99mTc(III)复合体[99mTc(S-R)(CDO)(CDOH)2B-Me] (R=P1-24) 。巯基S将使Tc(III)核更加稳定，延长心脏滞留；聚醚基R可降低肝脏摄取，提高心脏滞留。通过改变聚醚基长度得到心肌摄取高和显像特性最理想的产品。采用SD大鼠体内分布及动态平面显像进行评价筛选。预期得到心肌摄取高、首次提取高、滞留时间长，肝脏摄取低，比现有显像剂显像特性更加理想的心肌灌注显像剂。

现今临床应用最广的心肌灌注显像剂是99mTc-Sestamibi和99mTc-Tetrofosmin，显像特性不够理想，心肌摄取及首次提取较低，而肝脏摄取高。99mTc-Teboroxime 在现有显像剂中心肌摄取及首次提取最高，且心肌摄取和心肌血流在很大范围具有良好线性关系，但心脏滞留时间太短，无法满足心肌显像。本项目拟对99mTc-Teboroxime进行修饰，制备8种新型99mTc(III)复合体[99mTc(S-R)(CDO)(CDOH)2 B-Me] (R=P1-24) 。然而标记产物标记率较低，放射性化学纯度不高，只有40~60%，未能达到预期设想要求。我们并未因此放弃研究，在不改变最终目标的基础上更改实验方案。一方面将S-R配体基团换为F，SCN和N3，另一方面更换不同的“硼酸帽” [isoxazol-4-yl (IS)、N-methyl-pyridinium (MP)、pyrazol-3-yl (PA)、pyridin-3-yl (PY)、uracil-5-yl(5U)]进行心肌显像剂摄取机理的研究，探讨新型99mTc(III)复合体[99mTcL(CDO)(CDOH)2B-R] (L = Cl , F, SCN, N3；R = IS, MP, PA, PY, 5U)的物理、化学以及生物学特性。研究结果表明配体集团和“硼酸帽”均对99mTc(III)复合体的心肌摄取和心脏滞留时间有显著影响：其中99mTc-Teboroxime(N3) 和PAboroxime与 99mTc-Teboroxime心肌摄取相似，但半排时间明显延长。后期我们还合成了配体基团和“硼酸帽”双换的实验研究，发现[99mTcN3(CDO)(CDOH)2B-R] (R=IS, MP, PA, PY, 5U)较相应 [99mTcCl(CDO)(CDOH)2B-R] (R = IS, MP, PA, PY, 5U) 的HPLC保持时间均有所延长，初始心肌摄取基本相似，但心脏滞留时间更长。近期我们又尝试了新一批“硼酸帽”[99mTcCl(CDO) (CDOH)2B-R] (R = 2F, 3F, 5F, HP, MPY, PM, 4PY)研究，取得了很好的实验结果，其中以99mTc-5Fboroxime心肌显像性质（心肌摄取及心脏滞留时间）最佳，其最佳显像时间窗为注射后0-15分钟。

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