Preclinical evaluation of [¹⁸F]Mitophos_07 as an imaging agent for doxorubicin induced cardiotoxicity

Objectives: Chemotherapy-induced cardiotoxicity affects many cancer patients and has a significant impact on survival rate. Anthracyclines such as doxorubicin are amongst the most toxic to cardiac tissue and are widely used. Current techniques to identify chemotherapy-induced cardiotoxicity rely on echocardiography and heart ejection fractions. We hypothesis a that reduction of mitochondrial membrane potential (∆Ψ_m), as an early indication of a change in myocardial energetics, will precede observable decreases in function. Therefore, PET agents based on lipophilic cations sensitive to ∆Ψ_m may allow earlier diagnosis of cardiotoxicity, impacting treatment strategies. Herein we assess the potential of lipophilic cation [¹⁸F]Mitophos_07 as a possible imaging agent for chemotherapy-induced cardiotoxicity via an acute doxorubicin challenge.

Methods: The fully automated 2-step synthesis of [¹⁸F]Mitophos_07 occurs through copper-catalysed cycloaddition between [¹⁸F]fluoroethyl azide and the terminal alkyne group of the precursor, but-3-ynyl (tris-3,5-dimethylphenyl)phosphonium bromide.¹ SD rats (n=5-6 per group) received iv infusion of doxorubicin (10, 15 or 20 mg/kg, 3 ml/h) via tail vein, 48 h prior to [¹⁸F]Mitophos_07 injection (mean ± SD 6.30 ± 1.71 MBq). Cardiac radioactivity at 60 min post injection was determined by gamma counter measurements and expressed as standardised uptake values (SUV).

Results: [¹⁸F]Mitophos_07 was produced in >99 % radiochemical purity and good specific activity (68 ± 19 GBq/µmol). In vivo biodistribution in SD rats showed high myocardial uptake (SUV_60min: 5.29 ± 0.89), with rapid washout from liver and blood to give excellent myocardium to liver, blood and plasma ratios (9.02 ± 2.68, 76 ± 23 and 240 ± 136 respectively). Myocardial uptake was significantly reduced by acute doxorubicin treatment in a dose-dependent manner (maximum decrease, 35.8 ± 4.9 %, 20 mg/kg doxorubicin). A typical weight loss of 5-10 % was observed over the 48 h of doxorubicin treatment however no severe clinical signs were observed throughout the protocol.

Conclusion: Favorable biodistribution, including rapid liver washout, of [¹⁸F]Mitophos_07 gives potential advantages over other lipophilic cation radiotracers such as [¹⁸F]FBnTP and [^99mTc]Tc-MIBI which suffer from poor heart to liver ratios. Dose dependent decrease of myocardial uptake upon acute doxorubicin challenge and dynamic PET scan data indicates the potential of Mitophos_07 for imaging doxorubicin induced cardiotoxicity. Further studies on Langendorff perfused hearts, cardiac injury biomarkers and in vitro assays are ongoing. Research Support: ¹ Haslop, A. et al. Mol Pharm, 2014, 11, 3818-3822

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