Highly Efficient One-Pot Labeling of New Phosphonium Cations with Fluorine-18 as Potential PET Agents for Myocardial Perfusion Imaging

Abstract

Lipophilic cations such as phosphonium salts can accumulate in mitochondria of heart in response to the negative inner-transmembrane potentials. Two phosphonium salts [(18)F]FMBTP and [(18)F]mFMBTP were prepared and evaluated as potential myocardial perfusion imaging (MPI) agents in this study. The cations were radiolabeled via a simplified one-pot method starting from [(18)F]fluoride and followed by physicochemical property tests, in vitro cellular uptake assay, ex vivo mouse biodistribution, and in vivo rat microPET imaging. The total radiosynthesis time was less than 60 min including HPLC purification. The [(18)F] labeled compounds were obtained in high radiolabeling yield (∼50%) and good radiochemical purity (>99%). Both compounds were electropositive, and their log P values at pH 7.4 were 1.16 ± 0.003 (n = 3) and 1.05 ± 0.01 (n = 3), respectively. Both [(18)F]FMBTP and [(18)F]mFMBTP had high heart uptake (25.24 ± 2.97% ID/g and 31.02 ± 0.33% ID/g at 5 min postinjection (p.i.)) in mice with good retention (28.99 ± 3.54% ID/g and 26.82 ± 3.46% ID/g at 120 min p.i.). From the PET images in rats, the cations exhibited high myocardium uptake and fast clearance from liver and small intestine to give high-contrast images across all time points. These phosphonium cations were radiosynthesized via a highly efficient one-pot procedure for potential MPI offering high heart accumulation and rapid nontarget clearance.

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

“…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. [20][21][22][23][24][25] Recently, our group has synthesised the MitoPhos series of tracers, which are fluorine-18 radiolabelled alkyl-functionalised triarylphosphonium (TAP) cations, in order to provide radiotracers with tunable lipophilicity. One example of this series is [ 18 F]MitoPhos_07, shown in Fig.…”

Synthesis and bioevaluation of 4-chloro-2-tert-butyl-5-[2-[[1-[2-[18F]fluroethyl]-1H-1,2,3-triazol-4-yl]methyl]phenylmethoxy]-3(2H)-pyridazinone as potential myocardial perfusion imaging agent with PET

“…Because the PET isotope 18 F has excellent nuclear properties, many efforts have been done to develop new 18 F‐labeled MPI agents. Several novel MPI agents, such as 18 F‐labeled lipophilic cations ( 18 F‐FBnTP, 18 F‐FERhB, 18 F‐FPTP, 18 F‐3, 18 F‐FETMP, 18 F‐TPP, and [ 18 F]FMBTP) and analogs of mitochondrial complex I (MC‐I) inhibitors ( 18 F‐RP1004 and BMS‐747158‐02) have been reported.…”

Phosphonium salts and P-ylides

“…71,72 Similarly, phosphonium salts were used as agents for PET imaging based on labelled 18 F compounds. [73][74][75][76][77][78][79][80][81][82] A structure-activity relationship study of a library of novel bifunctional Gd(III) complexes covalently bonded to arylphosphonium cations was reported by Morrison et al 83 Such complexes were designed for potential application in binary cancer therapies such as neutron capture and photon activation therapies. Mononuclear Cu(II) complexes of hydrazone ligands containing a triphenylphosphonium moiety were synthesized and characterized by Tan and co workers.…”