title: Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation.
abstract: With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [(11)C]1a, while identification of [(11)C]2a and [(11)C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.
authors.affiliation: †Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, Mont-Saint Aignan Cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohn
authors.affiliation: §CEA/DSV/I2BM, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Cedex Caen, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Gourand
authors.affiliation: †Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, Mont-Saint Aignan Cedex, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Papamicaël
authors.affiliation: §CEA/DSV/I2BM, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Cedex Caen, France.
authors.forename: Méziane
authors.initials: M
authors.lastname: Ibazizène
authors.affiliation: §CEA/DSV/I2BM, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Cedex Caen, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Dhilly
authors.affiliation: ‡VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gembus
authors.affiliation: ‡VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Alix
authors.affiliation: †Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, Mont-Saint Aignan Cedex, France.
authors.forename: Mihaela-Liliana
authors.initials: ML
authors.lastname: Ţînţaş
authors.affiliation: ‡VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Marsais
authors.affiliation: §CEA/DSV/I2BM, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Cedex Caen, France.
authors.forename: Louisa
authors.initials: L
authors.lastname: Barré
authors.affiliation: †Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, Mont-Saint Aignan Cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Levacher
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology; D002250:Carbon Radioisotopes / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002219:Carbamates; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D011355:Prodrugs
keywords: 11C-radiolabeling; Alzheimer’s disease; central acetylcholinesterase inhibitors; cyclic rivastigmine analogues; prodrug