Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.
JACC Cardiovasc Imaging. 2012 Apr;5(4):409-18. doi: 10.1016/j.jcmg.2011.10.008.
The aim of this study was to develop a molecular imaging strategy that can monitor myocardial angiotensin-converting enzyme (ACE)-1 upregulation as a function of progressive heart failure.
High-affinity technetium-99m-labeled lisinopril (Tc-Lis) has been shown to specifically localize in tissues that express ACE in vivo, such as the lungs. Whether Tc-Lis can also detect upregulation of ACE in the heart, by external in vivo imaging, has not been established.
Twenty-one ACE-1 over-expressing transgenic (Tg) and 18 wild-type control rats were imaged using in vivo micro single-positron emission computed tomography (SPECT)-computed tomography (CT) at 10, 30, 60, and 120 min after Tc-Lis injection. A subgroup of rats received nonradiolabeled (cold) lisinopril before the Tc-Lis injection to evaluate nonspecific binding. After imaging, the rat myocardium was explanted, ex vivo images were acquired, and percent injected dose per gram gamma-well was counted, followed by an assessment of enzyme-linked immunosorbent assay-verified ACE activity and messenger ribonucleic acid expression.
On micro SPECT-CT, myocardial ACE-1 uptake was best visualized in Tg rats at 120 min after Tc-Lis injection. The quantitative uptake of Tc-Lis in the myocardium was 5-fold higher in mutant Tg than in control rats at each time point after tracer injection. The percent injected dose per gram uptake was 0.74 ± 0.13 in Tg myocardium at 30 min and was reduced substantially to 0.034 ± 0.003% when pre-treated with cold lisinopril (p = 0.029). Enzyme activity assay showed a >30-fold higher level of ACE-1 activity in the myocardium of Tg rats than in controls. The ACE-1 messenger ribonucleic acid was quantified, and lisinopril was found to have no effect on ACE-1 gene expression.
The Tc-Lis binds specifically to ACE, and the activity can be localized in Tg rat hearts that over-express human ACE-1 with a signal intensity that is sufficiently high to allow external imaging. Such a molecular imaging strategy may help identify susceptibility to heart failure and may allow optimization of pharmacologic intervention.
本研究旨在开发一种分子影像学策略，以监测心肌血管紧张素转换酶（ACE）-1 的上调，作为进行性心力衰竭的功能指标。
高亲和力锝-99m 标记的赖诺普利（Tc-Lis）已被证明可特异性定位于体内表达 ACE 的组织，如肺部。Tc-Lis 是否也可以通过体外活体成像检测心脏中 ACE 的上调尚未确定。
21 只 ACE-1 过表达转基因（Tg）和 18 只野生型对照大鼠在 Tc-Lis 注射后 10、30、60 和 120 分钟进行体内微单正电子发射计算机断层扫描（SPECT）-计算机断层扫描（CT）成像。一部分大鼠在 Tc-Lis 注射前接受非放射性（冷）赖诺普利以评估非特异性结合。成像后，取出大鼠心肌，进行离体图像采集，并计算每克γ井的注入剂量百分比，然后评估酶联免疫吸附试验验证的 ACE 活性和信使核糖核酸表达。
在微 SPECT-CT 上，在 Tc-Lis 注射后 120 分钟，Tg 大鼠的心肌 ACE-1 摄取最佳。在示踪剂注射后每个时间点，突变 Tg 大鼠心肌 Tc-Lis 的摄取量比对照大鼠高 5 倍。Tg 心肌的每克摄取剂量在 30 分钟时为 0.74±0.13%，当用冷赖诺普利预处理时，摄取量大大降低至 0.034±0.003%（p=0.029）。酶活性测定显示 Tg 大鼠心肌 ACE-1 活性高出对照大鼠 30 倍以上。定量测定 ACE-1 信使核糖核酸，发现赖诺普利对 ACE-1 基因表达无影响。
Tc-Lis 特异性结合 ACE，并且可以在过表达人 ACE-1 的 Tg 大鼠心脏中定位其活性，信号强度足以进行外部成像。这种分子成像策略可能有助于确定心力衰竭的易感性，并可能允许优化药物干预。
