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.

Keywords: 18F-Fluoroalkylphosphonium cations; Mitochondrial voltage sensors; Myocardial imaging agents; Positron emission tomography; Tetraphenylphosphonium cation derivatives.

Fig. 1

Schematic structure of radioisotope labeled tetraphenylphosphonium cation derivatives. a ¹¹C-triphenylmethylphosphonium cation (¹¹C-TPMP), b (4-¹⁸F-fluorophenyl)triphenylphosphonium cation (¹⁸F-TPP), c (3-¹⁸F-fluoropropyl)triphenylphosphonium cation, d 4-¹⁸F-fluorobenzyltriphenylphosphonium cation (¹⁸F-FBnTP), e 4-¹⁸F-fluorobenzyltris 4-dimethylaminophenylphosphonium cation, f (5-¹⁸F-fluoropentyl)triphenylphosphonium cation (¹⁸F-FPTP), g (6-¹⁸F-fluorohexyl)triphenylphosphonium cation (¹⁸F-FHxTP), h (7-¹⁸F-fluoroheptyl)triphenylphosphonium cation (¹⁸F-FHtTP), i (8-¹⁸F-fluorooctyl)triphenylphosphonium cation (¹⁸F-FOTP), j (2-(2-¹⁸F-fluoroethoxy)ethyl)triphenylphosphonium cation (¹⁸F-FETP), k (2-(2-¹⁸F-fluoroethoxy)ethyl)tris(4-methoxyphenyl)phosphonium cation (¹⁸F-FETMP), l ⁶⁴Cu-(4-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1 yl)methyl)benzyl)triphenylphosphonium cation, m ⁶⁴Cu-(2-(diphenylphosphoryl)ethyl)diphenyl(4-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)benzyl)phosphonium cation

Fig. 2

Different radiosynthetic methods of ¹⁸F-TPP. a Direct ¹⁸F labeling method using 4-nitrophenyltriphenylphosphonium b Two step ¹⁸F labeling method using 4-iodophenyltrimethylammonium iodide

Fig. 3

Coronal microPET images of normal rats after intravenous injection of 37 MBq of a ¹³N-NH₃, b ¹⁸F-FPTP, c ¹⁸F-FHTP, d ¹⁸F-FETP and e ¹⁸F-FETMP. The heart is visible, with excellent heart-to-background contrast at each time point after radiotracer injection. H: heart; L: liver; SUV: standardized uptake value. (Reprinted with permission of Kim et al. [–31, 34])

Fig. 4

Short-, vertical long-, and horizontal long-axis and polar map images of a ¹³N-NH₃, b ¹⁸F-FPTP, c ¹⁸F-FHTP, or d ¹⁸F-FETP in each representative MI model. Data were collected between 0 to 10 and 20 to 30 minutes after radiotracer injection (37 MBq). (Reprinted with permission of Kim et al. [34])