Nasal absorption of (S)-UH-301 and its transport into the cerebrospinal fluid of rats.

Targeting the brain via nasal administration of drugs has been studied frequently over the last few years. In this study, the serotonin-1a receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropyl-amino) tetralin ((S)-UH-301) hydrochloride was used as a model substance. The systemic absorption and transport of (S)-UH-301 into male Sprague-Dawley rat cerebrospinal fluid (CSF) were investigated after nasal and intravenous administration. Blood and CSF samples were obtained at regular time intervals from the arteria carotis and by cisternal puncture, respectively, after administration to both nostrils (total 12 micromol/kg) or into the vena jugularis (6 micromol/kg). The concentrations of (S)-UH-301 in plasma and CSF were measured by HPLC with electrochemical detection. The maximum plasma concentration of intranasal (S)-UH-301 occurred in about 7 min and the absolute bioavailability seemed to be complete (F=1.2+/-0.4). Initially, no increased concentrations of (S)-UH-301 were seen in CSF after nasal compared to intravenous administration i.e. it appeared that no direct transport of (S)-UH-301 from the nasal cavity, along the olfactory neurons and into the CSF occurred. However, a prolonged duration of the concentration was seen after nasal administration of (S)-UH-301 and after about 20 min the CSF(na):CSF(iv) concentration ratio (corrected for different dosage) exceeded 1.

Blood-cerebrospinal fluid and blood-brain barriers imaged by 18F-labeled metabolites of 18F-setoperone studied in humans using positron emission tomography.

18F-Setoperone, a sensitive radioligand for brain serotonin 5-HT2 receptor positron emission tomography studies, is metabolized into 18F-labeled metabolites, which participate in blood 18F radioactivity. Its main metabolite, identified as reduced 18F-setoperone, was synthesized and studied in humans to determine if 18F-labeled metabolites of 18F-setoperone (a) enter into the brain, (b) bind to the 5-HT2 receptor, and (c) explain the increase of 18F radioactivity in the free fraction in blood measured following 18F-setoperone injection. After reduced 18F-setoperone injection, the brain-to-blood 18F radioactivity concentration ratio (a) was low, at the beginning, indicating that this metabolite did not cross the blood-brain barrier; (b) was increased thereafter, with a higher radioactivity level in the choroid plexus than in brain tissue, suggesting a blood-CSF barrier crossing due to radioligand hydrophilicity; and (c) showed similar kinetics for cerebellum and frontal cortex, indicating that radioactive metabolites of 18F-setoperone did not bind to the 5-HT2 receptor. Because hydrophilic 18F-labeled metabolites of 18F-setoperone increased 18F radioactivity in the free fraction in blood, we quantified the relation between 18F-setoperone metabolism and free fraction kinetics in blood. A significant negative correlation was found between metabolism and free fraction rate constants in blood, showing it was possible to predict the 18F-setoperone metabolism rate using free fraction kinetics in blood. This will allow us to avoid the use of radio-TLC, a reference method that is difficult to use when multiple samples must be analyzed. A hydrophilic positron-emitter radioligand could also be used to study the blood-CSF barrier.

Evidence for the existence of serotonin uptake inhibitor-like substances in human cerebrospinal fluid.

Addition of human cerebrospinal fluid (CSF) induced a marked inhibition of 3H-paroxetine binding to the monkey cortical membranes, while the specific binding of 3H-imipramine was slightly inhibited. Moreover, 3H-serotonin (5-hydroxy-tryptamine, 5-HT) uptake inhibition in the monkey cortical synaptosomes was also increased as the volume of added CSF was increased. Scatchard analysis of specific 3H-paroxetine binding with human CSF showed non-competitive kinetics, although CSF was competitive with 3H-imipramine binding. The inhibitory effect of human CSF on 5-HT uptake was non-competitive in nature. The endogenous substances in human CSF most probably act at the recognition site labeled with 3H-paroxetine. Moreover, occupation of this site by the endogenous substances is likely to inhibit the 5-HT uptake process.

Alaproclate a novel antidepressant? A biochemical and clinical comparison with zimeldine.

Clinical and biochemical effects of two selective 5-HT uptake inhibitors, zimeldine and alaproclate, were studied in 24 hospitalized patients with endogenous depression. According to a randomized parallel group design 14 patients were treated with zimeldine and 10 with alaproclate. The dosage of both zimeldine and alaproclate was 200 mg daily. For the evaluation of the clinical effect, Montgomery & Asberg Depression Rating Scale (MADRS) was used. Seven of 14 patients treated with zimeldine and seven of 10 treated with alaproclate improved. 5-HT uptake inhibition in patients' platelets and concentration of amine metabolites (5-HIAA, HVA, HMPG) in CSF were studied before and during treatment. After 3 weeks of treatment with zimeldine 5-HIAA and HMPG in CSF decreased significantly while HVA in CSF increased significantly. Zimeldine produced a significant 5-HT uptake inhibition in platelets. During treatment with alaproclate no significant change in amine metabolites concentration in CSF was found and there were no mean changes on 5-HT uptake inhibition in platelets.