Abstract
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Introduction: Acute myocardial infarction (MI) is the most common cause of mortality worldwide. For an effective treatment, non-invasive imaging is needed for assessing the status of altered perfusion in the infarcted heart. Positron emission tomography (PET) tracers currently employed are limited by their shorter half-life resulting in the need for multiple productions and complex radiochemistry facility. Recently, we reported radiolabeling of cardiac targeting peptide with 68Ga and evaluated it in healthy CD1 mice. In this study, we evaluated [68Ga]Ga-NOTA-CTP in CD1 mice with MI to show its application in the non-invasive diagnosis of a MI.
Methods: CTP is a 12-amino acid cell-penetrating peptide that targets cardiomyocytes developed by Zahid et al. The radiosynthesis and formulation of [68Ga]Ga-NOTA-CTP was previously reported by Pandey et al. In this study, the radiochemical stability of [68Ga]Ga-NOTA-CTP was evaluated in mouse (n = 2) and human sera (n = 2) at 37 °C at 0 min, 30 min, 60 min and 120 min post-incubation by rad-TLC using iTLC-SG paper and 0.1 M sodium citrate (pH = 5.1) as a mobile phase. For in vivo studies, MI was initiated in 6-8 weeks old CD1 mice by ligating the left descending artery. The [68Ga]Ga-NOTA-CTP (3.21±0.10 MBq, n=5) was injected into the tail vein of normal CD1 mice (n=2) and CD1 mice with MI (~10 d post-surgery, n=3) obtained from Envigo, Indianapolis, IN. After administration of [68Ga]Ga-NOTA-CTP, the animals underwent a dynamic PET scan for 30 min followed by 7 min CT scan using Siemens Inveon PET/CT system. Dynamic imaging was followed by static PET/CT scans at 60 min and 120 min post injection. The acquired images were visualized and analyzed using MIM 7.2.7 software (MIM Software Inc., Cleveland, OH). After imaging at 120 min, the animals were euthanized, and organs harvested for ex vivo biodistribution analysis.
Results: [68Ga]Ga-NOTA-CTP was synthesized with >96 % radiochemical purity with molar activity (Am) of 1.53±0.3 GBq/μmol (n = 7). [68Ga]Ga-NOTA-CTP showed relatively higher stability of 91.71±0.53 % at 120 min post incubation in mouse serum as compared to 88.43±1.06 % stability at 120 min post incubation in human serum. Noninvasive PET/CT imaging showed lower average uptake (SUV = 0.77 ± 0.15; p value < 0.05, n = 3) of [68Ga]Ga-NOTA-CTP in infarcted heart during 0-7 min as compared to normal heart (SUV =1.01±0.22, n = 2, Figure 1A). Additionally, within the infrared heart, the ratio of uptake of [68Ga]Ga-NOTA-CTP in the ligated left ventricle (LV) over whole heart (LV/WH) showed lower uptake than the unligated right ventricle (RV) over whole heart (RV/WH) normalized at 4, 5, 8 and 15 mins (Figure 1B). Ex vivo biodistribution performed at 120 min post injection showed [68Ga]Ga-NOTA-CTP to be primarily present in excretory organs in both normal and infarcted CD1 mice.
Conclusions: Present study demonstrates differential uptake of [68Ga]Ga-NOTA-CTP in infarcted heart over normal heart in CD1 mice, with significantly lower uptake in ligated heart over unligated heart (p value <0.05). Additional lower ratio of uptake of [68Ga]Ga-NOTA-CTP was observed in LV/WH versus RV/WH, further demonstrating effect of ligation in left ventricle. Obtained results are promising and warrant further study to translate [68Ga]Ga-NOTA-CTP in humans. Acknowledgement: This study was funded by the Department of Radiology and Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA.
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