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 [ 18 F]fluoride. The use of the nosylate precursor and tetra-n-butyl ammonium [ 18 F]fluoride ([ 18 F]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 [ 18 F]7 in mice revealed a fast metabolic degradation with the formation of radiometabolites which have been detected in the brain.

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…For PET studies of PDE5 in the brain in particular, the INSERM branch at Clermont-Ferrand, France, developed in cooperation with our group the novel radioligand [ 18 F]17 [73] (see Figure 4). Based on our first PDE5 radioligand [ 18 F]ICF24027 [1,74] ([ 18 F]18, Figure 4) reported in 2016, structural modifications have been done to improve the metabolic stability by introducing the fluorine-containing moiety in another position of the molecule [73,81]. Out of a series of PDE5-specific quinoline-based ligands, compound 17 is the most promising derivative (Figure 4).…”

“…Out of a series of PDE5-specific quinoline-based ligands, compound 17 is the most promising derivative (Figure 4). Since nucleophilic 18 F-labeling of a secondary carbon is challenging, two strategies regarding an appropriate leaving group have been pursued, via the tosylate and the nosylate precursor [73] (see Scheme 9). Interestingly, highest radiochemical yields for automated radiosynthesis of [ 18 F]17 were achieved by using the nosylate precursor and [ 18 F]TBAF with the addition of small amounts of water to the reaction mixture [73].…”

“…Since nucleophilic 18 F-labeling of a secondary carbon is challenging, two strategies regarding an appropriate leaving group have been pursued, via the tosylate and the nosylate precursor [73] (see Scheme 9). Interestingly, highest radiochemical yields for automated radiosynthesis of [ 18 F]17 were achieved by using the nosylate precursor and [ 18 F]TBAF with the addition of small amounts of water to the reaction mixture [73]. 4) have been published by collaborating research groups from Hebei, China, and Indiana, USA [75,77].…”

“…The radioligands In vitro autoradiography on porcine brain slices revealed moderate binding of [ 18 F]17 in cerebellum, cortex and hippocampus [73] that are regions with identified PDE5 expression in the human brain [69]. Only a 10-25% decrease of [ 18 F]17 accumulation in all investigated brain areas has been achieved using sildenafil [78][79][80] (see Figure 4) or compound 17 (1 µM of each) as blocking agents indicating high non-specific binding of the radioligand [73]. We assume that the inhibitory potency of [ 18 F]17 might be too low due to the poor expression of PDE5 in the brain and thus, radioligands with subnanomolar potency might be needed for accurate PDE5 imaging in that regard.…”

Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer's disease

“…There is a growing interest in design and evaluation of new PET radiotracers for in vivo imaging of PDEs including PDE2, PDE4, PDE5, PDE7 and PDE10 (Andrés et al, 2012;Schröder et al, 2016). In this project of new tracer development, we focus on PDE5 as target, because there are strong preclinical evidences suggesting that PDE5 may serve as a clinically relevant biomarker and a disease-relevant drug/imaging agent target in AD (Liu et al, 2016;Wenzel et al, 2019). Several PDE5 radioligands have been developed, and representative carbon-11 and fluorine-18 labeled PDE5 inhibitors with an IC50 value < 1 nM are shown in Figure 1, however, so far no successful detection of PDE5 in the brain for quantification of its expression or occupancy has been reported (Chekol et al, 2014;Schröder et al, 2016).…”