Abstract
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Objectives Changes in mitochondrial bioenergetics and the loss of mitochondrial membrane potential can be early indicators of pathophysiology. Lipophilic phosphonium cations have been shown to accumulate within mitochondria and offer a route to image mitochondrial bioenergetics in vivo. We compare the kinetics of two radiolabelled phosphonium cations, [18F]MitoPhos_04 [A] and [18F]MitoPhos_07 [B].
Methods Radioligands were synthesized through a copper-catalysed cycloaddition reaction between [18F]fluoroethyl azide and the terminal alkyne group of the corresponding precursor. In vitro radioligand assays were performed in murine B-cell lymphoma, naïve and treated with Cisplatin (24hrs,100μM). In vivo evaluations were performed using naïve SD rats (n=3-4), which received iv administrations of 9MBq of [18F][A] or [18F][B] to determine biodistribution and ligand kinetics.
Results In vitro, cellular uptakes of 50% and 5% were observed for [18F][A] and [18F][B] respectively. The uptake of both ligands was decreased by 70-80% after Cisplatin treatment. In vivo, [18F][A] was excreted by a hepatobillary route, whereas [18F][B] was also excreted by a renal route. For both radioligands, activity accumulated in tissues with a high proliferative capacity, such as the hematopoietic system. [18F][B] demonstrated a greater accumulation in the myocardium and thyroid (SUV60min:4.7±1.5 and 17.4±13 respectively) compared with [18F][A] (SUV60min:0.6±0.06 and 4.2±2 respectively). Both ligands reached a rapid pseudo-equilibrium (<20mins) in the bone marrow, thyroid and myocardium.
Conclusions In vitro data is consistent with the theory that uptake of [18F][A] and [18F][B] is sensitive to treatment with pro-apoptotic agents. Both ligands rapidly reached a pseudo-equilibrium in vivo. The initial differences in cellular accumulation and the preferential accumulation of [18F][B] in myocardial and thyroid tissues warrant further investigation, as well as a comparison in isolated mitochondrial preparations.
Research Support GSK Imanova Ltd