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

Barbara Wenzel (1) , Jianrong Liu , Sladjana Dukic-Stefanovic (2) , Winnie Deuther-Conrad (1) , Rodrigo Teodoro (1) , Friedrich-Alexander Ludwig (1) , Jean-Michel Chezal (3, 4) , Emmanuel Moreau (4) , Peter Brust (1) , Aurelie Maisonial-Besset (4)

1 Institute of Radiopharmaceutical Cancer Research
2 Leipzig University / Universität Leipzig
3 IMTV - Imagerie Moléculaire et Thérapie Vectorisée
4 IMoST - Imagerie Moléculaire et Stratégies Théranostiques

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.

Keywords: (18)F-fluoroazetidine; (18)F-radiolabeling; PDE5; 18 F-radiolabeling; nosylate; tosylate; 18 F-fluoroazetidine 2

Domains: Cancer

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, 2019, 86, pp.346-362. ⟨10.1016/j.bioorg.2019.01.037⟩. ⟨hal-02090315⟩