In Vitro and In Vivo Evaluations of Dihydroquinoline- and Dihydroisoquinoline-based Targetor Moieties for Brain-specific Chemical Delivery Systems

Abstract

Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.

A 11C-Labeled 1,4-Dihydroquinoline Derivative as a Potential PET Tracer for Imaging of Redox Status in Mouse Brain

“…Thus, [ 11 C]DHQ1 responded to the changes of redox status in mouse brain homogenate. A previous study has shown that unlabeled DHQ1 was stable in rat brain homogenate without any sign of oxidation within the time of experiment (6 hours), 9 whereas our study showed that [ 11 C]DHQ1 was rapidly oxidized in mouse brain homogenate (Figure 2). This may be due to species differences in the activity of enzymes involved in the oxidation of DHQ1 between mouse and rat.…”

“…This compound was synthesized by the hydrolysis of quinoline-3-carbonitrile in the same manner as described previously. 9 3-Carbamoyl-1-methylquinolinium iodide (Q1 + ). This compound was synthesized by the reaction of quinoline-3-carboxamide with CH 3 I in the same manner as described previously.…”

“…This compound was synthesized by the reaction of quinoline-3-carboxamide with CH 3 I in the same manner as described previously. 9 1-Methyl-1,4-dihydroquinoline-3-carboxamide (DHQ1). This compound was prepared following a modified literature procedure.…”

“…8 1,4-Dihydropyridine and 1,4-dihydroquinoline are the analogs of NADH/NADPH and have been used as redox carriers in chemical delivery systems for delivery of therapeutic drugs to the brain. [9][10][11] Similar to the oxidation of NADH or NADPH, 1,4-dihydropyridine and 1,4-dihydroquinoline derivatives are oxidized to the corresponding quaternary ammonium ions by biological redox systems. In contrast to previous tracers for detecting ROS, we hypothesized that such derivatives labeled with a PET nuclide could provide information on brain redox status by the mechanism shown in Figure 1A.…”

Pharmacokinetic Mechanism Involved in the Prolonged High Retention of Laninamivir in Mouse Respiratory Tissues after Intranasal Administration of its Prodrug Laninamivir Octanoate

“…A similar prodrug approach has been advocated by Bodor et al (2002), for drug-targeting of blood-brain barrier. They showed that several hydrophilic compounds including opioid peptides were successfully delivered to the central nervous system by using specific prodrug approaches (Prokai et al, 1999;Bodor et al, 2002;Tapfer et al, 2004), one of which was to incorporate a lipophilic ester into the active form for the increase of permeability through blood-brain barrier and the retention of the generated active form within the target site.…”