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  • Conventional aromatic radiofluorination via nucleophilic sub


    Conventional aromatic radiofluorination via nucleophilic substitution requires electron-withdrawing activating group(s) at the ortho or para position to achieve good radiolabeling yield. In the case of CJ-042794 (), the phenoxy substitution para to the fluoro group is considered an electro-donating group, and therefore, it deactivates the aromatic nucleophilic substitution reaction using F-fluoride. Recently, Gouverneur’s and Scott’s groups reported copper-mediated aromatic radiofluorination reactions using arylboronic cgrp antagonist synthesis pinacol esters as corresponding precursors. Such radiofluorination reactions work well even with electron-rich arenes. Due to relative ease for the preparation of arylboronic acid pinacol ester precursor, the copper-mediated aromatic radiofluorination strategy was selected for the synthesis of F-CJ-042794. The arylboronic acid pinacol ester precursor for the synthesis of F-CJ-042794 was prepared following procedures depicted in . 4-Bromophenol was first treated with sodium hydride in -dimethylformamide (DMF) to generate phenoxide, and then reacted with methyl 2-fluoro-5-chlorobenzoate to form methyl 2-(4-bromophenoxy)-5-chlorobenzoate in 59% yield. Methyl benzoate was hydrolyzed in a mixture of methanol, tetrahydrofuran and aqueous sodium hydroxide solution to obtain the benzoic acid quantitatively. Benzoic acid was treated with ,-dicyclohexylcarbodiimide (DCC) and 2,3,5,6-tetrafluorophenol to form an activated 2,3,5,6-tetrafluorophenyl ester that was subsequently coupled with methyl 4-[(1)-1-aminoethyl]benzoate to obtain the benzamide in 91% yield. The bromo group on benzamide was converted to boronic acid pinacol ester via Pd-catalyzed Miyaura borylation reaction, and the desired fluorination precursor was obtained in 79% yield. As depicted in , F-CJ-042794 was synthesized in two steps: a copper-mediated aromatic radiofluorination reaction followed by base hydrolysis. For the radiofluorination reaction, we followed the reaction conditions (1:5:125 precursor:Cu(OTf):pyridine in DMF, 110°C, 20min) optimized by Scott’s group. These optimized conditions previously enabled us to prepare a promising myocardial perfusion PET tracer 4-[F]fluorobenzyltriphenylphosphonium (F-FBnTP) in one-step from its pinacol ester precursor in ∼60% radiochemical conversion yield. However, in this study, the F-fluorination yield using arylboronic pinacol ester precursor was much lower. Following HPLC purification, F-CJ-042794 was obtained in only 1.5±1.1% (n=2) decayed-corrected radiochemical yield with 99.9±29.6GBq/μmol specific activity and >99% radiochemical purity. Despite the lower yield, the amount of F-CJ-042794 obtained was sufficient for imaging and biodistribution studies. Therefore, no further attempts were made to increase the radiochemical yields of F-CJ-042794. It should be noted that Zischler et al. recently reported that using primary or secondary alcohol as a co-solvent can improve radiochemical yields of copper-mediated radiofluorination reactions. Under their optimized conditions, the use of -butanol as a co-solvent resulted in almost quantitative (>95%) F-fluorination of arylboronic pinacol esters even for electron-rich indoles. With F-CJ-042794, we first measured its stability in mouse plasma. Aliquots of F-CJ-042794 were incubated with mouse plasma at 37°C. At pre-determined time points, the mixtures were diluted with acetonitrile, centrifuged, and the supernatants were analyzed by HPLC., , As shown in , no noticeable decomposition of F-CJ-042794 was observed over 1h, demonstrating high stability of F-CJ-042794 in mouse plasma. Next, to evaluate the potential of F-CJ-042794 as an imaging agent, we conducted PET/CT imaging and biodistribution studies in mice bearing LNCaP prostate cancer xenografts that express EP4 receptor., The time-activity curves of F-CJ-042794 in LNCaP tumour and various organs/tissues derived from the 1h dynamic imaging study are shown in . The radioactivity in the heart (as a representative of blood) peaked at the first minute post-injection (p.i.) to ∼30%ID/g, followed by rapid clearance in the next minute to 13%ID/g, and slower clearance afterwards. Although with much lower uptake values, the uptake patterns of brain and bone were very similar to that of heart (blood): peaked within the first minute p.i., rapidly decreased in the next min, and cleared slowly subsequently. The radioactivity in the liver peaked at 2min p.i. to ∼33%ID/g, followed by sustained uptake at the same level for the next 5min, and then slow clearance thereafter. The uptake values of kidney and muscle reached their highest levels at ∼5min, and decreased continuously afterwards. The uptake of F-CJ-042794 into tumour increased over time in the first 20min p.i. and reached its highest level at ∼2%ID/g. Minimal radioactivity was cleared from the tumour until the conclusion of the scan, increasing the contrast of tumour-to-muscle over time (see B)