Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870. METHODS: The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned. RESULTS: Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (Tmax) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred. CONCLUSION: HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.

Monoamine Oxidase Inhibitors (MAOIs) in Psychiatric Practice: How to Use them Safely and Effectively.

Monoamine oxidase inhibitors (MAOIs) were among the first licensed pharmacological treatments for patients with depression but over time have fallen out of mainstream clinical use. This has led to a loss of clinician training opportunities and reduced availability of MAOIs for prescribing. This article provides a concise and practical overview of how to use MAOIs safely and effectively in psychiatric practice. We consider the history of MAOIs, why they are not used more frequently, their mechanisms of action, availability, indications and efficacy, general tolerability, withdrawal symptoms, and safety considerations (including hypertensive reactions and serotonin syndrome). Practical advice is given in terms of dietary restrictions, interactions with other medications (both prescribed and non-prescribed), and how prescribers can stop and switch MAOIs, both within the drug class and outside of it. We also provide advice on choice of MAOI and treatment sequencing. Lastly, we consider emerging directions and potential additional indications.

Acetylcholinesterase and monoamine oxidase-B inhibitory activities by ellagic acid derivatives isolated from Castanopsis cuspidata var. sieboldii.

Among 276 herbal extracts, a methanol extract of Castanopsis cuspidata var. sieboldii stems was selected as an experimental source for novel acetylcholinesterase (AChE) inhibitors. Five compounds were isolated from the extract by activity-guided screening, and their inhibitory activities against butyrylcholinesterase (BChE), monoamine oxidases (MAOs), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were also evaluated. Of these compounds, 4'-O-(α-L-rhamnopyranosyl)-3,3',4-tri-O-methylellagic acid (3) and 3,3',4-tri-O-methylellagic acid (4) effectively inhibited AChE with IC50 values of 10.1 and 10.7 µM, respectively. Ellagic acid (5) inhibited AChE (IC50 = 41.7 µM) less than 3 and 4. In addition, 3 effectively inhibited MAO-B (IC50 = 7.27 µM) followed by 5 (IC50 = 9.21 µM). All five compounds weakly inhibited BChE and BACE-1. Compounds 3, 4, and 5 reversibly and competitively inhibited AChE, and were slightly or non-toxic to MDCK cells. The binding energies of 3 and 4 (- 8.5 and - 9.2 kcal/mol, respectively) for AChE were greater than that of 5 (- 8.3 kcal/mol), and 3 and 4 formed a hydrogen bond with Tyr124 in AChE. These results suggest 3 is a dual-targeting inhibitor of AChE and MAO-B, and that these compounds should be viewed as potential therapeutics for the treatment of Alzheimer's disease.

Synthesis of new hydrazone derivatives and evaluation of their monoamine oxidase inhibitory activity.

A novel series of hydrazone derivatives were designed and synthesized. Their structures were characterized by IR, 1H NMR, 13C NMR and HR-MS spectroscopic methods. The newly synthesized compounds were evaluated for their inhibitory activity against monoamine oxidase enzymes (MAO-A and MAO-B). Compounds 2a, 2k, 4a and 4i showed significant inhibitory activity against MAO-A, with IC50 value in the range of 0.084-0.207 µM compared to reference drug moclobemide (IC50 value = 6.061 µM). These compounds (2a, 2k, 4a and 4i) were exposed to cytotoxicity tests to establish their preliminary toxicological profiles and were found to be non-cytotoxic. Moreover, the most effective compound 4i was evaluated using enzyme kinetics and docking studies to elucidate the plausible mechanisms of inhibition of MAO-A. According to enzyme kinetic studies, compound 4i was a reversible and competitive inhibitor with similar inhibition features as the substrates. Also, it was seen that this compound was settled down very properly at the active site of MAO-A enzyme by doing important interactions owing to the docking studies. Finally, ADME predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. According to calculated ADME predictions, all parameters of the compounds were within the standard ranges in terms of "Rule of Five" and "Rule of Three" and it was detected that the synthesized compounds (2a-4i) have good and promising pharmacokinetic profiles.

Microemulsion-based gel for the transdermal delivery of rasagiline mesylate: In vitro and in vivo assessment for Parkinson's therapy.

Rasagiline mesylate (RSM) is a selective and irreversible monoamine oxidase B inhibitor used for the treatment of Parkinson's disease (PD). However, its unfavorable biopharmaceutical properties, such as extensive degradation in the gastrointestinal tract and first-pass metabolism are responsible for its low oral bioavailability and suboptimal therapeutic efficacy. Here, we report the feasibility of delivering RSM via the transdermal route using RSM containing microemulsion-based gel (RSM-MEG) to achieve effective management of PD. Our in vitro skin permeation studies of RSM-MEG showed significantly higher (at least ~1.5-fold) permeation across rat skin compared to the conventional RSM hydrogel. Our skin irritation studies in rabbits showed that RSM-MEG is safe for transdermal application. Finally, using the rat model of rotenone-induced Parkinsonism, we demonstrated that the topical application of RSM-MEG was equally effective in reversing PD symptoms when compared to oral RSM therapy. Thus, our study confirmed the feasibility and potential of transdermal delivery of RSM via simple topical application of RSM-MEG, and this approach could be an alternative therapeutic intervention for the treatment of Parkinson's disease.

First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat.

BACKGROUND: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. OBJECTIVES: The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. METHODS: This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. RESULTS: No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. CONCLUSIONS: Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses. TRIAL REGISTRATION: EUDRACT No. 2015-003721-33, filed 30 October 2015.

Near-Infrared Monoamine Oxidase Inhibitor Biodistribution in a Glioma Mouse Model.

PURPOSE: The biodistribution imaging kinetics of near-infrared monoamine oxidase inhibitor (NMI) are reported here. METHODS: NMI was administered intravenously or orally to mice and detected by NIR fluorescence optical imaging within minutes and the longitudinal signal distribution was measured for up to 1 week after a single dose. RESULTS: NMI rapidly reached 3.7-fold higher ventral and 3.2-fold higher brain region fluorescent signal intensity compared to oral route at 24 h. Similar patterns of NMI biodistribution were found in mice with or without intracranial implanted GL26 brain tumors. NMI was highly associated with tumors in contrast to adjacent non-tumor brain, confirming diagnostic utility. NMI 5 mg/kg imaging signal in brain at 48 h was optimal (tumor/non-tumor ratio > 3.5) with minimum off-target distribution. Intravenous NMI imaging signal peaked between 24 h and 48 h for lung, liver, kidney, blood, brain, and most other tissues. Clearance (signal weaker, but still present) from most tissues occurred by day 7. Intravenous low dose (0.5 mg/kg) minimally labeled tumor and other tissues, 5 mg/kg showed optimal imaging signal in glioma at a dose we previously reported as efficacious, and 50 mg/kg was tolerable but saturated the tissue signals beyond tumor specificity. Gel electrophoresis showed two major bands present in brain tumor and tissue protein lysates. CONCLUSIONS: Intravenous 5 mg/kg was optimal dose to target brain tumor and identified off-target organs of concern: lungs, liver, and kidneys. These results demonstrate the biodistribution and optimal dose range of NMI for treatment and diagnostic monitoring of glioma.

New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors.

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 µM, Selectivity Index (SI): 9.70 × 10-4), 7 (0.009 µM, SI: 4.55 × 10-5), 14 (0.001 µM, SI: 8.00 × 10-4), 21 (0.009 µM, SI: 1.37 × 10-5), and 42 (0.010 µM, SI: 5.40 × 10-6), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.

Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.

Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT6R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.

Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson's disease.

Introduction: Parkinson's disease is a chronic, neurodegenerative disease entity with heterogeneous features and course. Levodopa is the most efficacious dopamine substituting drug. Particularly, long-term application of oral levodopa/decarboxylase inhibitor formulations sooner or later supports onset of fluctuations of movement. It also shifts levodopa turnover to O-methylation, which impairs human methylation capacity and increases oxidative stress.Areas covered: This narrative review summarizes pharmacokinetic and pharmacodynamic features of available levodopa cotherapies on the basis of a literature search with the terms L-dopa, inhibitors of catechol-O-methyltransferase and monoamine oxidase-B.Expert opinion: Long-term levodopa/dopa decarboxylase inhibitor application with concomitant inhibition of both, catechol-O-methyltransferase and monoamine oxidase-B supports a more continuous dopamine substitution, which ameliorates fluctuations of motor behavior. This triple combination also enhances both, antioxidative defense and methylation capacity. Inhibition of monoamine oxidase-B reduces generation of oxidative stress in the brain. Constraint of catechol-O-methyltransferase reduces homocysteine synthesis due to diminished consumption of methyl groups for levodopa turnover at least in the periphery. An additional nutritional supplementation with methyl group donating and free radical scavenging vitamins is recommendable, when future drugs are developed for long-term levodopa/dopa decarboxylase treated patients. Personalized medicine treatment concepts shall also consider nutritional aspects of Parkinson's disease.

Treatment of Parkinson's Disease by MAO-B Inhibitors, New Therapies and Future Challenges - A Mini-Review.

BACKGROUND: One of the most prevalent neurodegenerative diseases with increasing age is Parkinson's disease (PD). Its pathogenesis is unclear and mainly confined to glutamate toxicity and oxidative stress. The dyskinesia and motor fluctuations and neuroprotective potential are the major concerns which are still unmet in PD therapy. OBJECTIVE: This article is a capsulization of the role of MAO-B in the treatment of PD, pharmacological properties, safety and efficiency, clinical evidence through random trials, future therapies and challenges. CONCLUSION: MAO-B inhibitors are well tolerated for the treatment of PD because of their pharmacokinetic properties and neuroprotective action. Rasagiline and selegiline were recommended molecules for early PD and proven safe and provide a modest to significant rise in motor function, delay the use of levodopa and used in early PD. Moreover, safinamide is antiglutamatergic in action. When added to Levodopa, these molecules significantly reduce the offtime with a considerable improvement of non-motor symptoms. This review also discusses the new approaches in therapy like the use of biomarkers, neurorestorative growth factors, gene therapy, neuroimaging, neural transplantation, and nanotechnology. Clinical evidence illustrated that MAOB inhibitors are recommended as monotherapy and added on therapy to levodopa. A large study and further evidence are required in the field of future therapies to unwind the complexity of the disease.

Pharmacokinetics, Pharmacodynamics, and Safety of a Single Escalating Dose and Repeated Doses of Rasagiline Transdermal Patch in Healthy Chinese Subjects.

A rasagiline transdermal patch can be used to offer continuous rasagiline to patients with Parkinson's disease who cannot take their usual oral medications. This was the first study to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects. Thirty subjects were randomized to 3 groups with 10 subjects in each group. The 10 subjects of group 1 received a single 1-mg dose of rasagiline as a tablet; the 20 subjects of groups 2 and 3 received a single transdermal patch (48-hour patch-on period) containing 1.25 mg and 2.5 mg rasagiline, respectively. After a 2-week washout period, the subjects of group 1 were assigned to receive 1 mg of rasagiline tablets every 24 hours for 7 days, and the subjects of group 2 were assigned to receive 1.25-mg rasagiline transdermal patches (48-hour patch-on period) every 72 hours for 5 time periods. The absorption of rasagiline from the transdermal patch was significantly improved, although the peak plasma concentration was obviously reduced. There was slight accumulation of rasagiline dose after multiple administrations. Inhibition of platelet monoamine oxidase-B (MAO-B) activity was dose dependent. The 80% inhibition maintained for at least 48 hours after multiple-dose administration of 1 mg tablets, and for 72 hours after multiple-dose administration of 1.25 mg/48 h patch. Compared with rasagiline tablets, the transdermal patch had a prolonged duration of 80% inhibition and increased maximal inhibition of MAO-B activity. These characteristics permitted an interval of 3 days of dosing, which was convenient for patients to use.

New role for crinamine as a potent, safe and selective inhibitor of human monoamine oxidase B: In vitro and in silico pharmacology and modeling.

ETHNOPHARMACOLOGICAL RELEVANCE: The development of selective inhibitors of monoamine oxidase B (MAO-B) has been essential in treating Parkinson's disease. However, the apparent hepatotoxicity and drug-drug interactions of current inhibitors accentuate the need for the development of novel pharmacotherapies. Crossyne guttata (L.) D. & U. Müll-Doblies is used frequently by Rastafarian bush doctors to treat alcoholism, a disorder which is also accentuated by MAO. OBJECTIVE: The study sought to isolate, identify and characterise the biologically active constituents of C. guttata based on their ability to inhibit the MAO enzymes. MATERIALS AND METHODS: Column chromatography was used to isolate the biologically active alkaloids of C. guttata. The ability of the alkaloids to inhibit the biotransformation of 4-aminoantipyrine by the MAO enzymes was evaluated in vitro. In silico docking was conducted using AutoDock Vina server while the pharmacokinetic properties of the compounds were evaluated using SwissADME. RESULTS: Chromatographic separation of an ethanolic fraction of C. guttata yielded the alkaloids crinamine 1 and epibuphanisine 2. 1 and 2 along with structurally related alkaloids haemanthamine 3 and haemanthidine 4 were evaluated for their ability to inhibit the action of isozymes of MAO in vitro. Alkaloids effected submicromolar IC50 values against MAO-B, the most potent of which being crinamine 1 (0.014 µM) > haemanthidine 4 (0.017 µM) > epibuphanisine 2 (0.039 µM) > haemanthamine 3 (0.112 µM). Binding energies of the alkaloids correlated well with their inhibitory potential with crinamine displaying the best binding efficacy and binding energy score with MAO-B. DISCUSSION AND CONCLUSION: Crinamine and epibuphanisine exhibited potent and selective inhibitory activity towards MAO-B. After comprehensive in silico investigations encompassing robust molecular docking analysis, the drug-like attributes and safety of the alkaloids suggest the crinamine is a potentially safe drug for human application.

Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer's disease and other tauopathies.

PURPOSE: Tau deposition is a key pathological feature of Alzheimer's disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aß) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies. Several PET tracers targeting tau deposits have been discovered and tested in humans. Limitations have been reported, especially regarding their selectivity. METHODS: In our screening campaign we identified pyrrolo[2,3-b:4,5-c']dipyridine core structures with high affinity for aggregated tau. Further characterization showed that compounds containing this moiety had significantly reduced monoamine oxidase A (MAO-A) binding compared to pyrido[4,3-b]indole derivatives such as AV-1451. RESULTS: Here we present preclinical data of all ten fluoropyridine regioisomers attached to the pyrrolo[2,3-b:4,5-c']dipyridine scaffold, revealing compounds 4 and 7 with superior properties. The lead candidate [18F]PI-2620 (compound 7) displayed high affinity for tau deposits in AD brain homogenate competition assays. Specific binding to pathological misfolded tau was further demonstrated by autoradiography on AD brain sections (Braak I-VI), Pick's disease and progressive supranuclear palsy (PSP) pathology, whereas no specific tracer binding was detected on brain slices from non-demented donors. In addition to its high affinity binding to tau aggregates, the compound showed excellent selectivity with no off-target binding to Aß or MAO-A/B. Good brain uptake and fast washout were observed in healthy mice and non-human primates. CONCLUSIONS: Therefore, [18F]PI-2620 was selected for clinical validation.

Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases.

A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC50 values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide (3) was identified as a lead AChE inhibitor with IC50 =0.052±0.006 µm. N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide (2) was the lead MAO-B inhibitor with IC50 =0.034±0.007 µm, and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B.

Monoamine oxidase B (MAO-B), predominantly expressed in glial cells, plays an important role in neurotransmitter regulation, and MAO-B activity relates to several neuronal diseases. Here, we aimed to develop a radiofluorinated MAO-B imaging probe based on the structure of a selective MAO-B inhibitor, MD-230254. We synthesized and evaluated a series of compounds in vitro and in vivo. A series of fluorinated analogs of MD-230254 were synthesized and evaluated for inhibitory potency and selectivity toward MAO-B. 5-[4-(2-[18 F]Fluorobenzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (2-[18 F]FBPO) was synthesized from a corresponding tributylstannyl precursor and [18 F]CH3 COOF. Biodistribution after intravenous injection of 2-[18 F]FBPO was evaluated in male ddY mice with or without pretreatment by inhibitors. Among the compounds synthesized and evaluated, 2-FBPO showed high inhibitory potency and selectivity toward MAO-B comparable with MD-230254. 2-[18 F]FBPO was successfully synthesized by an electrophilic reaction with a high radiochemical purity of more than 99%. 2-[18 F]FBPO was efficiently taken up by the brain and showed rapid blood clearance, which provided a brain/blood radioactivity ratio of 3.7 at 90 minutes postinjection. The brain radioactivity was significantly decreased by pretreatment with an MAO-B selective inhibitor. The great potential of 2-[18 F]FBPO as an MAO-B imaging probe, applicable to a variety of diseases, is indicated.