Imaging of Chemotherapy-Induced Acute Cardiotoxicity with ¹⁸F-Labeled Lipophilic Cations

Abstract

Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation positron emission tomography (PET) tracers may be suitable for early detection of cardiotoxicity. This study aims to evaluate an 18 F-labelled lipophilic phosphonium cation e.g. 18 F-Mitophos, as a cardiac imaging agent, comparing it to leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin (DOX) model. MethodsCardiac uptake and response to decreased mitochondrial membrane potential (ΔΨm) of 18 F-Mitophos and 99m Tc-Sestamibi were tested in isolated perfused rat hearts. Baseline pharmacokinetic profiles of 18 F-Mitophos and 18 F-FBnTP and their response to acute DOXinduced cardiotoxicity were assessed in rats in vivo (10, 15 or 20 mg/kg DOX, i.v., 48 h prior).by Roger Gunn on July 8, 2019. For personal use only. jnm.snmjournals.org Downloaded from ResultsCardiac retention of 18 F-Mitophos was over double that of 99m Tc-Sestamibi in isolated perfused rat hearts. Favourable biodistribution of 18 F-Mitophos in vivo was observed with heart to tissue ratios of 304  186, 11.2  1.2 and 3.8  0.6 for plasma, liver and lung respectively (60 min). A significant dose-dependent loss of cardiac retention of 18 F-Mitophos was observed upon DOX treatment where average cardiac SUV30-60 (mean  SD) decreased from 3.5  0.5 (control) to 1.8  0.1 (DOX 20 mg/kg). Other biomarkers assessed showed no alterations.Conclusions 18 F-Mitophos showed suitable pharmacokinetic parameters for cardiac imaging. A significant dose-response of cardiac uptake to DOX treatment was observed before detectable biomarker alterations. It is therefore, a promising tracer for imaging chemotherapy-induced cardiotoxicity. This is the first demonstration of PET radiolabelled lipophilic cations being used for the imaging of chemotherapy-induced cardiotoxicity imaging and indicates the potential application of these compounds in this area.

PET Tracers for Imaging Cardiac Function in Cardio-oncology

“…A recent study highlights the possibility of visualizing disrupted mitochondrial membrane potential by PET. In this study, cardiac retention of a radiolabeled phosphonium cation, [ 18 F]MitoPhos, decreases in a dose-dependent manner in rat hearts following doxorubicin treatment [47]. The decrease in retention in the left ventricle was nearly twofold in comparison to controls and preceded detectable changes in cardiac troponins.…”

In-vivo Imaging of Mitochondrial Depolarization of Myocardium With Positron Emission Tomography and a Proton Gradient Uncoupler

“…In the case of chronic macroscopic tissue injury, there is probably a mixture of mitochondrial states, those with complete collapse of mitochondrial membrane potential and cell death, others with partial depolarization, and still others that are essentially normal. However, for applications such as early detection of cardiotoxicity, the ability to detect partial depolarization of myocardial mitochondria may be important for managing such injuries before depolarization leads to irreversible injury (McCluskey et al, 2019).…”

New Insights in Early Detection of Anticancer Drug-Related Cardiotoxicity Using Perfusion and Metabolic Imaging

“…Similarly, new radiopharmaceuticals have been developed to assess early DOX myocardial cardiotoxicity detection, such as 18 F-labeled lipophilic cation PET tracers (144). Its principle is to image mitochondrial damage by 18 F-labeled lipophilic tracers, which diffuse across mitochondrial membranes depending upon the mitochondrial membrane potential (144).…”

“…Similarly, new radiopharmaceuticals have been developed to assess early DOX myocardial cardiotoxicity detection, such as 18 F-labeled lipophilic cation PET tracers (144). Its principle is to image mitochondrial damage by 18 F-labeled lipophilic tracers, which diffuse across mitochondrial membranes depending upon the mitochondrial membrane potential (144). The tracers will therefore accumulate in cardiac tissue in case of mitochondrial damage, which is one of the possible mechanisms of myocardial cardiotoxicity of DOX, allowing early detection of its cardiotoxicity.…”