Molecular Function and Imaging Program, National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y4W7.
Nucl Med Biol. 2011 Oct;38(7):1059-66. doi: 10.1016/j.nucmedbio.2011.04.002. Epub 2011 Aug 9.
Abnormal sympathetic nervous system and β-adrenoceptor (β-AR) signaling is associated with diabetes. [(3)H]CGP12177 is a nonselective β-AR antagonist that can be labeled with carbon-11 for positron emission tomography. The aim of this study was to examine the suitability of this tracer for evaluation of altered β-AR expression in diabetic rat hearts.
Ex vivo biodistribution with [(3)H]CGP12177 was carried out in normal Sprague-Dawley rats for evaluation of specific binding and response to continuous β-AR stimulation by isoproterenol. In a separate group, high-fat-diet feeding imparted insulin resistance and a single intraperitoneal injection of streptozotocin (STZ) or vehicle evoked hyperglycemia (blood glucose >11 mM). [(3)H]CGP12177 biodistribution was assessed at 2 and 8 weeks post-STZ to measure β-AR binding in heart, 30 min following tracer injection. Western blotting of β-AR subtypes was completed in parallel.
Infusion of isoproterenol over 14 days did not affect cardiac binding of [(3)H]CGP12177. Approximately half of rats treated with STZ exhibited sustained hyperglycemia and progressive hypoinsulinemia. Myocardial [(3)H]CGP12177 specific binding was unchanged at 2 weeks post-STZ but significantly reduced by 30%-40% at 8 weeks in hyperglycemic but not euglycemic STZ-treated rats compared with vehicle-treated controls. Western blots supported a significant decrease in β(1)-AR in hyperglycemic rats.
Reduced cardiac [(3)H]CGP12177 specific binding in the presence of sustained hyperglycemia corresponds to a decrease in relative β(1)-AR expression. These data indirectly support the use of [(11)C]CGP12177 for assessment of cardiac dysfunction in diabetes.
异常的交感神经系统和β-肾上腺素能受体（β-AR）信号与糖尿病有关。[(3)H]CGP12177 是一种非选择性的β-AR 拮抗剂，可以用碳-11 标记进行正电子发射断层扫描。本研究的目的是研究这种示踪剂在评估糖尿病大鼠心脏中改变的β-AR 表达的适用性。
在正常 Sprague-Dawley 大鼠中进行 [(3)H]CGP12177 的离体生物分布研究，以评估其对异丙肾上腺素持续β-AR 刺激的特异性结合和反应。在另一组中，高脂饮食引起胰岛素抵抗，单次腹腔注射链脲佐菌素（STZ）或载体引起高血糖（血糖>11 mM）。在 STZ 后 2 和 8 周评估 [(3)H]CGP12177 的生物分布，以测量心脏中的β-AR 结合，在示踪剂注射后 30 分钟进行。同时完成β-AR 亚型的 Western 印迹。
异丙肾上腺素输注 14 天不会影响 [(3)H]CGP12177 在心脏中的结合。大约一半接受 STZ 治疗的大鼠表现出持续的高血糖和进行性的低胰岛素血症。STZ 治疗后 2 周时，心肌 [(3)H]CGP12177 的特异性结合没有改变，但在高血糖但非正常血糖的 STZ 治疗大鼠中，8 周时降低了 30%-40%，与载体治疗的对照组相比。Western 印迹支持高血糖大鼠中β(1)-AR 显著减少。
在持续高血糖存在的情况下，心脏 [(3)H]CGP12177 的特异性结合减少与相对β(1)-AR 表达的减少相对应。这些数据间接支持使用 [(11)C]CGP12177 评估糖尿病中的心脏功能障碍。
