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

Abstract

This study reports the synthesis and characterization of 4-chloro-2-tert-butyl-5-[2-[[1-[2-[(18) F]fluroethyl]-1H-1,2,3-triazol-4-yl]methyl]phenylmethoxy]-3(2H)-pyridazinone ([(18) F]Fmp2) for myocardial perfusion imaging (MPI). The tosylate precursor and non-radioactive compound [(19) F]Fmp2 were synthesized and characterized by infrared, (1) H-NMR, (13) C-NMR, and mass spectra (MS). The radiotracer [(18) F]Fmp2 was obtained by one-step nucleophilic substitution of tosyl with (18) F, and evaluated as an MPI agent in vitro and in vivo. Starting from [(18) F]KF/K222 solution, the typical decay-corrected radiochemical yield (RCY) was 38 ± 8.8% with high radiochemical purity (>98%). The specific activity was calculated as 10 GBq/µmol at the end of synthesis determined by HPLC analysis. In the mice biodistribution, [(18) F]Fmp2 showed very high initial heart uptake (53.35 ± 5.47 %ID/g at 2 min after injection) and remarkable retention. The heart/liver, heart/lung, and heart/blood ratios were 7.98, 8.20, and 53.13, respectively at 2 min post-injection. In the Positron Emission Tomography (PET) imaging study of Chinese mini-swine, the standardized uptake value of the liver decreased modestly during the 2 h post-injection, while the heart uptake and heart/liver ratios continued to increase with time. [(18) F]Fmp2 exhibited good stability, high heart uptake and low lung uptake in mice and Chinese mini-swine. It may be worthy of further modification to improve liver clearance for MPI in the future.

Synthesis and Evaluation of 18F-labeled Pyridaben Analogues for Myocardial Perfusion Imaging in Mice, Rats and Chinese mini-swine

“…Thus, the signal-noise ratios of [ 18 F]Fmpp2 are more ideal, particularly at subsequent time points. Compared with [ 18 F]Fmp2 25 , the PEGylated tracer [ 18 F]Fmpp2 has obvious faster liver clearance, which is consistent with our previous reports 22 23 . For [ 18 F]Fmp2, its liver uptake in mice increased with time (55% increase at 60 min p.i.…”

“…Previously, our group reported a series of pyridaben analogues as potential MPI agents 22 23 24 25 . [ 18 F]FP1OP exhibits the most promising biological properties with high initial heart uptake and good target-to-background ratios.…”

“…However, its moderate instability in water limits its possibility to be an ideal MPI agent 23 . The following compounds [ 18 F]FPTP2 22 and [ 18 F]Fmp2 25 have excellent stabilities. However, their liver clearance is slow, and thus the heart/liver ratios are not ideal.…”