Targeting cyclic nucleotide phosphodiesterase 5 (PDE5) in brain: Toward the development of a PET radioligand labeled with fluorine-18

Abstract : With the aim to develop a specific radioligand for imaging the cyclic nucleotide phosphodiesterase 5 (PDE5) in brain by positron emission tomography (PET), seven new fluorinated inhibitors (3-9) were synthesized on the basis of a quinoline core. The inhibitory activity for PDE5 together with a panel of other PDEs was determined in vitro and two derivatives were selected for IC50 value determination. The most promising compound 7 (IC50 = 5.92 nM for PDE5A), containing a 3-fluoroazetidine moiety, was further radiolabeled by aliphatic nucleophilic substitution of two different leaving groups (nosylate and tosylate) using [18F]fluoride. The use of the nosylate precursor and tetra-n-butyl ammonium [18F]fluoride ([18F]TBAF) in 3-methyl-3-pentanol combined with the addition of a small amount of water proved to be the best radiolabeling conditions achieving a RCY of 4.9 ± 1.5% in an automated procedure. Preliminary biological investigations in vitro and in vivo were performed to characterize this new PDE5 radioligand. Metabolism studies of [18F]7 in mice revealed a fast metabolic degradation with the formation of radiometabolites which have been detected in the brain.
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https://hal.archives-ouvertes.fr/hal-02090315
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Submitted on : Thursday, April 4, 2019 - 4:19:08 PM
Last modification on : Thursday, September 5, 2019 - 5:00:11 PM

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Barbara Wenzel, Jianrong Liu, Sladjana Dukic-Stefanovic, Winnie Deuther-Conrad, Rodrigo Teodoro, et al.. Targeting cyclic nucleotide phosphodiesterase 5 (PDE5) in brain: Toward the development of a PET radioligand labeled with fluorine-18. Bioorganic Chemistry, Elsevier, 2019, 86, pp.346-362. ⟨10.1016/j.bioorg.2019.01.037⟩. ⟨hal-02090315⟩

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