Radiolabeled Phosphonium Salts as Mitochondrial Voltage Sensors for Positron Emission Tomography Myocardial Imaging Agents

Abstract

Despite substantial advances in the diagnosis of cardiovascular disease, (18)F-labeled positron emission tomography (PET) radiopharmaceuticals remain necessary to diagnose heart disease because clinical use of current PET tracers is limited by their short half-life. Lipophilic cations such as phosphonium salts penetrate the mitochondrial membranes and accumulate in mitochondria of cardiomyocytes in response to negative inner-transmembrane potentials. Radiolabeled tetraphenylphosphonium cation derivatives have been developed as myocardial imaging agents for PET. In this review, a general overview of these radiotracers, including their radiosynthesis, in vivo characterization, and evaluation is provided and clinical perspectives are discussed.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…485,718,719 Subsequently, a myriad of other analogs, varying the hydrophobicity of the alkyl linker connecting the fluorine-18 atom and the TPP + were synthesized and tested in heart models. 214,485,720–729 Results showed a preferential uptake of the TPP + -based PET agents in the heart with enhanced heart-to-lung ratios in mice one h after injection. 729 …”

Synthesis, gallium-68 radiolabelling and biological evaluation of a series of triarylphosphonium-functionalized DO3A chelators

“…Following general procedure 3, the title compound was prepared from 3c (0.33 g, 0.32 mmol) and trifluoroacetic acid (3.3 mL) as a white solid (0.17 g, 57%). 1 H NMR (400 MHz, MeOD) δ H ( ppm): 7.52 (3H, s, p-Ar), 7.49 (2H, d, 3 J HH = 7.7 Hz, C 6 H̲ 4 ), 7.18 (6H, d, 3 J HP = 13.1 Hz, o-Ar), 7.00 (2H, d, 3…”

“…They can accumulate in the mitochondrial matrix in a manner dependent on mitochondrial membrane potential (ΔΨ m ), which in normally functioning mitochondria is between 150-180 mV. [1][2][3][4] In lipophilic cations that have been successfully used as probes of ΔΨ m , the charge is delocalised over a large molecular surface area and as such, the tracers can pass easily through the lipid bilayer membrane. 2 Application of the Nernst equation to monocations predicts 100-to 500-fold accumulation compared to the extracellular space, and at 37°C, mitochondrial uptake of lipophilic cations increases 10-fold for every 61.5 mV increase in ΔΨ m .…”

“…TPP is widely known to target mitochondria since the cationic charge nominally residing on the phosphorus atom can be delocalised around the aromatic rings. 3,4,17,18 The first PET tracer to utilise TPP was designed by Fukuda et al and consisted of TPP methylated with carbon-11 (methylTPP). 19 Since then, there have been many different types of TPP-functionalised PET tracers for mitochondrial imaging, most commonly using fluorine-18 since its longer half-life facilitates clinical imaging.…”

“…= 3.9 Hz, o-Ar), 134.3 (d,2 J CP = 10.4 Hz, p-Ar), 132.0 (d,3 J CP = 5.7 Hz, C̲ 6 H 4 ), 130.4 (d,3 J CP = 3.4 Hz, m-Ar), 129.5 (d,4 J CP = 3.6 Hz,C̲ 6 H 4 ), 128.1 (d, 2 J CP = 8.6 Hz, C̲ 6 H 4 ), 114.6 (d, 1 J CP = 88.7 Hz, i-Ar), 33.1 (C̲ H 2 Br), 30.9 (d, 1 J CP = 48.1 Hz, C̲ H 2 P), 22.0 (C̲ H 3 ). 31 P{ 1 H}-NMR (162 MHz, CDCl 3 ) δ P ( ppm): 22.4.…”