Synthesis and in vitro evaluation of new fluorinated quinoline derivatives with high affinity for PDE5: Towards the development of new PET neuroimaging probes

Abstract

The increasing incidence of Alzheimer's disease (AD) worldwide is a major public health problem. Current treatments provide only palliative solutions with significant side effects. Therefore, new efficient treatment options and novel early diagnosis tools are urgently needed. Recently, strong pre-clinical evidences suggested that phosphodiesterase 5 (PDE5) may be clinically relevant both as biomarker and drug-target in AD. In this study, we intended to develop a new radiofluorinated tracer for the visualisation of PDE5 in brain using PET imaging. Based on currently known PDE5 inhibitors, a series of novel fluorinated compounds bearing a quinoline core have been synthesised via multi-steps reaction pathways. Their affinity for PDE5 and selectivity over other PDE families have been investigated. According to the data collected from this in vitro screening, fluorinated derivatives 24a, b bearing a fluoroethoxy group at the C-3 position of the quinoline core appeared to be the most promising structures and will be further radiolabelled with fluorine-18 for in vitro and in vivo evaluations as PET radiotracer for neuroimaging of PDE5.

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

“…However, the formation of the desired fluorinated product 16 could not be observed and only a by-product, identified as compound 17, was obtained with a yield of 57%. We assume that the formation of this stable six-membered ring in 17 is a result of an intramolecular cyclization caused by the electron donor effects of the free secondary amine located at the C-4 position of the quinoline, as previously observed during the chemical modifications at the "east region" of this compound class [28]. Therefore, an alternative strategy (Scheme 2, strategy 2) was developed, in which the amine at the C-4 position of 14 was beforehand protected using di-tert-butyl dicarbonate (Boc2O) in the presence of catalytic amounts of N,N-4-dimethylaminopyridine (DMAP) to obtain 18 with a yield of 74%.…”

“…Moreover, the influence of a combination of different substituents on positions C-6 and C-8 of the quinoline scaffold was studied resulting in the so far most potential candidates 1 [25] and 2 [26]. Based on these results, we started our attempts to introduce a fluorine containing structural moiety at the "east region" of 1 and 2 by substituting the hydroxymethyl group on C-3 by a fluoroethyl and fluoroethoxymethyl group [28], resulting in the development of the new PDE5 radioligand [ 18 F]ICF24027 [29]. However, due to the fast formation of a brain-penetrable radiometabolite, this radiotracer was not suitable for PDE5 imaging in brain.…”

“…The synthesis of derivatives 3 and 4 bearing modifications in the "north region" of the quinoline scaffold, started with the coupling of amine 10a with the 4-chloroquinoline 11 via aromatic nucleophilic substitution at the C-4 position of the quinoline ring (Scheme 1). 4-Chloroquinoline 11 was prepared as previously described by our group [28]. The necessary amine 10a was synthesized in 5 steps according to known procedures (see supporting information).…”

“…The desired fluorinated compounds 3 and 4 were obtained by a selective reduction of the ester function with lithium tri-tert-butoxyaluminum hydride (LTBA). For the synthesis of compounds 5-9 modified at the C-8 position of the quinoline core, two different palladium-catalyzed reaction pathways were developed in order to form the C-C bond in 5 and the C-N bond in 6-9 starting from compound 14 [28]. The synthesis of 5 started with the reaction of allyl alcohol with 9-borabicyclo[3.3.1]nonane (9-BBN) in tetrahydrofuran to afford the corresponding boronic ester, generated in situ at the α-position of the alkene reactant.…”

“…With an IC50 value of 5.92 nM compound 7 showed the highest inhibitory potential which is comparable to sildenafil (IC50 = 6.23 nM). Although the inhibitory activity of 7 is slightly lower compared to our first developed radiotracer [ 18 F]ICF24027 [28,29], this compound demonstrated a good selectivity toward the other PDEs and was therefore selected for 18 F-labeling to generate a potential radiotracer for PET imaging of PDE5A.…”