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 ¹⁸F for imaging by PET and characterized its in vivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with ¹⁸F a quinazolinone derivative ([¹⁸F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [¹⁸F]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 [¹⁸F]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 [¹³N]NH₃ PET. Results: 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 [¹⁸F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [¹⁸F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [¹⁸F]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. Conclusion: [¹⁸F]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.

肽激素生长素释放肽在心肌细胞中产生，并通过心肌生长激素促分泌素受体 （GHSR） 发挥作用，促进心肌细胞存活。生长素释放肽的给药可能对心肌梗死 （MI） 后结局有治疗作用。因此，需要开发分子成像探针，可以跟踪健康和疾病中 GHSR 的动力学，以更好地预测基于生长素释放肽的疗法的有效性。我们设计了一种用 ¹⁸F 标记的高亲和力 GHSR 配体，用于 PET 成像，并在 MI 的犬模型中表征了其体内特性。方法：我们合理设计并用 ¹⁸F 放射性标记了对 GHSR 具有亚纳摩尔结合亲和力的喹唑啉酮衍生物 （[¹⁸F]LCE470）。我们使用 PET/MRI 确定了 [¹⁸F]LCE470 在手术诱导的 MI 犬模型中的敏感性以及体内和离体特异性，这允许示踪剂摄取的解剖定位和同时确定整体心脏功能。[¹⁸F]LCE470 的摄取是通过时间-活动曲线和 SUV 分析在左心室的 3 个区域（梗死面积、左回旋支冠状动脉服务的区域和远端心肌）在 1.5 年的时间内确定的。通过 [¹³N]NH₃ PET 跟踪心脏灌注的变化。结果：在 0.33 nM 时测量 LCE470 的受体结合亲和力，这是已知对放射性标记的 GHSR 配体的最高受体结合亲和力。健康猎犬的体内封闭研究和心肌组织的离体封闭研究表明 [¹⁸F]LCE470 的特异性，示踪剂摄取与 GHSR 丰度之间的正相关证明了敏感性。 [¹⁸F]LCE470 摄取的 MI 后变化与灌注示踪剂分布和整体心脏功能的变化无关。我们发现 [¹⁸F]LCE470 在 MI 后 1 d 内左心室的区域分布显着分化，并在研究的整个 1.5 年持续时间内保持这种状态。结论： [¹⁸F]LCE470 是一种高亲和力 PET 示踪剂，可以检测心肌梗死后心肌 GHSR 区域分布的变化。GHSR 全球动力学的体内 PET 分子成像可能导致基于 GHSR 的疗法在治疗 MI 后重塑方面得到改进。