Radiosynthesis and preliminary biological evaluation of a new ¹⁸F‐labeled triethylene glycol derivative of triphenylphosphonium

Abstract

Delocalized lipophilic cations such as [(18)F]fluorobenzyltriphenylphosphonium ([(18)F]FBnTP) can accumulate in mitochondria and have been used in myocardial perfusion imaging (MPI). In this study, we established a simplified method for [(18)F]FBnTP synthesis using triphenylphosphine hydrobromide (PPh3 •HBr) without preparing an intermediate that contains benzyl bromide structure. Applying this new method, we synthesized and evaluated a novel (18)F-labeled PEGylated BnTP derivative ([(18)F]FPEGBnTP). In vitro cellular uptake study demonstrated that [(18)F]FPEGBnTP accumulated in cells in proportion to the relative intensity of mitochondrial membrane potential. Biodistribution study revealed that the heart : liver uptake ratio of [(18)F]FPEGBnTP (4.00 at 60 min) was superior to that of [(18)F]FBnTP (1.50 at 60 min). However, [(18)F]FPEGBnTP showed slow blood clearance and high radioactivity uptake in bone at 120-min post-injection. These results imply the possibility of [(18)F]FPEGBnTP being used as a MPI agent. However, there is a need of further structural optimization and flow-dependent uptake study.

Avenues to molecular imaging of dying cells: Focus on cancer

“…Changes in [ 18 F]FBnTP uptake may be difficult to interpret since the accumulation of this tracer can be affected by cellular efflux processes driven by multidrug‐resistance proteins and by tissue‐dependent differences of background uptake. Various structural analogs of [ 18 F]FBnTP have also been prepared, such as 4‐[ 18 F]‐tetraphenylphosphonium (TPP), ([ 18 F]fluoropentyl)triphenylphosphonium, and [ 18 F]PEGylated‐BnTP . Uptake of these compounds is probably affected by the same processes as the tissue uptake of [ 18 F]FBnTP.…”

“…235 The signal of the tracer has been reported to be stable up to 45 min after injection. 236 Changes in [ 18 F]FBnTP uptake may be difficult to interpret since the accumulation of this tracer can be affected by cellular efflux processes driven by multidrug-resistance proteins 237 242 Uptake of these compounds is probably affected by the same processes as the tissue uptake of [ 18 F]FBnTP.…”

One-step synthesis of 4-[18F]fluorobenzyltriphenylphosphonium cation for imaging with positron emission tomography

“…Recently, Ravert et al reduced the amount of reagents and synthesis time for the first 3 reaction steps by using microwave‐assisted heating . Tominaga et al reported the direct coupling of 4‐[ 18 F]fluorobenzyl alcohol with PPh 3 ·HBr to form 18 F‐FBnTP (Figure ), and the overall number of reaction steps was reduced to 3 . However, such multistep approach remains a challenge for implementing the synthesis of 18 F‐FBnTP for routine clinical studies.…”

“…Synthesis procedures for the preparation of 18 F‐FBnTP reported by A, Ravert et al; B, Tominaga et al; and C, this study…”

“…6 Tominaga et al reported the direct coupling of 4-[ 18 F]fluorobenzyl alcohol with PPh 3 ·HBr to form 18 F-FBnTP (Figure 1), and the overall number of reaction steps was reduced to 3. 7 However, such multistep approach remains a challenge for implementing the synthesis of 18 F-FBnTP for routine clinical studies. To simplify the synthesis, we investigated if 18 F-FBnTP could be prepared in one step via a recently reported copper-mediated 18 F-fluorination reaction with a pinacolyl arylboronate precursor ( Figure 1).…”