Imaging Research Program, Lawson Health Research Institute, London, Ontario, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
J Nucl Med. 2024 Oct 1;65(10):1633-1639. doi: 10.2967/jnumed.124.267578.
The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post-myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with F for imaging by PET and characterized its in vivo properties in a canine model of MI. We rationally designed and radiolabeled with F a quinazolinone derivative ([F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [F]LCE470 was determined by time-activity curve and SUV analysis in 3 regions of the left ventricle-area of infarct, territory served by the left circumflex coronary artery, and remote myocardium-over a period of 1.5 y. Changes in cardiac perfusion were tracked by [N]NH PET. The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. [F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.
肽激素 ghrelin 由心肌细胞产生，并通过心肌生长激素分泌受体（GHSR）发挥作用，促进心肌细胞存活。ghrelin 的给药可能对心肌梗死后（MI）结局有治疗作用。因此，需要开发能够跟踪健康和疾病中 GHSR 动态的分子成像探针，以更好地预测基于 ghrelin 的治疗方法的有效性。我们设计了一种高亲和力的 GHSR 配体，并用 F 标记，以便通过正电子发射断层扫描（PET）成像，并在 MI 的犬模型中对其体内特性进行了表征。我们合理设计并放射性标记了带有 F 的喹唑啉酮衍生物 ([F]LCE470)，对 GHSR 的结合亲和力为亚纳摩尔。我们使用 PET/MRI 在手术诱导的 MI 犬模型中确定了 [F]LCE470 的敏感性以及体内和体外特异性，这允许对示踪剂摄取的解剖定位和同时确定整体心脏功能。在 1.5 年的时间内，通过左心室区域（梗死面积）、左回旋支冠状动脉供血区和远程心肌的时间-活性曲线和 SUV 分析来确定 [F]LCE470 的摄取。通过 [N]NH PET 跟踪心脏灌注的变化。LCE470 的受体结合亲和力为 0.33 nM，这是已知的放射性标记 GHSR 配体的最高受体结合亲和力。在健康猎犬中的体内阻断研究和心肌组织中的体外阻断研究显示了 [F]LCE470 的特异性，并且通过示踪剂摄取与 GHSR 丰度之间的正相关证明了其敏感性。MI 后 [F]LCE470 摄取的变化独立于灌注示踪剂分布和整体心脏功能的变化。我们发现，MI 后 1 天内左心室内部的 [F]LCE470 分布区域明显分化，并在整个 1.5 年的研究过程中保持不变。[F]LCE470 是一种高亲和力的 PET 示踪剂，可检测 MI 后心肌 GHSR 区域性分布的变化。GHSR 整体动力学的体内 PET 分子成像可能会导致基于 GHSR 的治疗方法在治疗 MI 后重塑方面的改善。
