DOCSLIB.ORG

Substituted 3-Isobutyl-9, 10-Dimethoxy-1,3,4,6,7,11B

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Substituted 3-Isobutyl-9, 10-Dimethoxy-1,3,4,6,7,11B (19) TZZ Z_ 9B_T (11) EP 2 081 929 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) 09.01.2013 Bulletin 2013/02 (86) International application number: (21) Application number: 07864160.2 PCT/US2007/084176 (22) Date of filing: 08.11.2007 (87) International publication number: WO 2008/058261 (15.05.2008 Gazette 2008/20) (54) SUBSTITUTED 3-ISOBUTYL-9, 10-DIMETHOXY-1,3,4,6,7,11B-HEXAHYDRO-2H-PYRIDO[2,1-A] ISOQUINOLIN-2-OL COMPOUNDS AND METHODS RELATING THERETO SUBSTITUIERTE 3-ISOBUTYL-9,10-DIMETHOXY-1,3,4,6,7,11B-HEXAHYDRO-2H-PYRIDO[2,1-A] ISOCHINOLIN-2-OLVERBINDUNGEN UND DIESE BETREFFENDE VERFAHREN COMPOSÉS 3-ISOBUTYL-9, 10-DIMÉTHOXY-1,3,4,6,7,11B-HEXAHYDRO-2H-PYRIDO[2,1-A] ISOQUINOLIN-2-OL SUBSTITUÉS ET PROCÉDÉS ASSOCIÉS (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • BROSSIA ET AL: "SYNTHESEVERSUCHE IN DER HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE EMETIN-REIHE 3. MITTEILUNG 2-HYDROXY- SI SK TR HYDROBENZOÄAÜCHINOLIZINE" HELVETICA Designated Extension States: CHIMICA ACTA, VERLAG HELVETICA CHIMICA AL BA HR MK RS ACTA. BASEL, CH, vol. 41, no. 4, 1958, pages 1793-1806, XP008047475 ISSN: 0018-019X (30) Priority: 08.11.2006 US 864944 P • KILBOURN M R ET AL: "Absolute Configuration of (+)-alpha-Dihydrotetrabenazine, an Active (43) Date of publication of application: Metabolite of Tetrabenazine" CHIRALITY, WILEY- 29.07.2009 Bulletin 2009/31 LISS, NEW YORK, US, vol. 9, no. 1, 1997, pages 59-62, XP002329921 ISSN: 0899-0042 cited in the (73) Proprietor: NEUROCRINE BIOSCIENCES, INC. application San Diego, CA 92130 (US) • ARANDA ET AL.: "Synthesis and biological activity of iodinated and photosensitive (72) Inventor: GANO, Kyle, W. derivatives or tetrabenazine" EUREOPEAN San Diego, CA 92130 (US) JOURNAL OF MEDICINAL CHEMISTRY, vol. 25, 1990, pages 369-374, XP002471185 (74) Representative: Grünecker, Kinkeldey, Stockmair & Schwanhäusser Remarks: Leopoldstrasse 4 Thefile contains technical information submitted after 80802 München (DE) the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 081 929 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 081 929 B1 Description FIELD OF THE INVENTION 5 [0001] This invention relates generally to substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2ol compounds and their preparation. Also disclosed are methods of treating disorders by adminis- tration of such compounds to a warm-blooded animal in need thereof. BACKGROUND OF THE INVENTION 10 [0002] 3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, also known as tetrabenazine(TBZ), has beenused as a drug for decades.Tetrabenazine isa potent, reversibleinhibitor ofcatecholamine uptake by vesicular monoamine transporter-2 (VMAT2) (IC50 = 3.2 nM) (Scherman, et al, Proc.Natl. Acad. Sci. USA, (1983) 80:584-8) and is currently used in the treatment of various hyperkinetic movement disorders. Side effects asso- 15 ciatedwith TBZ include sedation,depression, akathisia,and parkinsonism. Inhibitionof VMAT2by TBZ resultsin depletion of brain monoamines in vivo (Pettibone, D.J. et al., Eur. J. Pharmacol. (1984) 102: 431-6). TBZ also inhibits presynaptic and postsynaptic dopamine receptors in rat brain (Login, I.S., et al., (1982) Ann. Neurology 12:257-62; Reches, et al, J. Pharmacol. Exp. Ther. (1983) 225: 515-521). This off- target activity of TBZ may be responsible for some of the observed side effects. 20 [0003] TBZ, which contains two chiral centers and is a racemic mix of two stereoisomers, is rapidly and extensively metabolized in vivo to its reduced form, 3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin- 2-ol, also known as dihydrotetrabenazine (HTBZ). HTBZ is thought to exist as four individual isomers: ( 6) alpha-HTBZ and (6) beta-HTBZ. The 2R, 3R, 11bR or (+) alpha-HTBZ is believed to be the absolute configuration of the active metabolite (Chirality 1997 9: 59-62). Despite its success in treating hyperkinetic disorders, tetrabenazine has a fairly low 25 and variable bioavailability. Tetrabenazine administration to humans is complicated by extensive first pass metabolism and little or no tetrabenazine is observed in the urine. [0004] There is a need in the art for analogs of tetrabenazine that provide the advantageous properties of tetrabenazine without exposing the body to all of stereoisomers of dihydrotetrabenazine. There is also a need for analogs of tetrabena- zine that exhibit a longer half- life than tetrabenazine. There is likewise a need in the art for analogs of tetrabenazine that 30 exhibit greater selectivity for VMAT2 than tetrabenazine. The present invention provides a tetrabenazine analog that exposes the body to a single stereoisomer of dihydrotetrabenazine, exhibits greater selectivity for VMAT2 than tetrabena- zine, exhibits a longer half- life than tetrabenazine, and may exhibit lower variability in dose required from patient to patient. [0005] A. Brossi et al., Helvetica Chimica Acta 1958, Vol. 41, No. 4, pages 1793 to 1806 describe the synthesis of 2- hydroxy-hydrobenzo[a]chinolizines; M. Kilbourn et al., Chirality 1997, Vol. 9, No. 1, pages 59 to 62 disclose the synthesis 35 of tetrabenazine and dihydrotetrabenazine derivatives and separation of the enantiomers by chiral column liquid chro- matography; G. Aranda et al., European Journal of Medicinal Chemistry, Vol. 25, 1990, pages 369 to 374 describe the synthesis of an iodinated derivative of tetrabenazine. BRIEF SUMMARY OF THE INVENTION 40 [0006] In brief, this invention is generally directed to substituted 3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-ol compounds, individual enantiomers thereof, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. More specifically, the substituted 3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compounds of this invention have the following 45 general structure (I): 50 55 including stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R1 is as defined below. [0007] The substituted isobutyl-3- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol com- 2 EP 2 081 929 B1 pounds of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders including the family of hyperkinetic movement disorders. Additionally these compounds may prove useful in the treatment of other disease states or conditions which are associated with inhibition of the vesicular monoamine transporter 2 (VMAT2). 5 [0008] The methods disclosed include administering an effective amount of a substituted 3- isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in still a further embodiment, pharmaceutical compositions are disclosed containing one or more substituted 3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compounds of this invention in combination with a pharmaceutically acceptable carrier and/or diluent. 10 [0009] These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions. [0010] The problem of the present invention is solved on the basis of claims 1 to 12. 15 BRIEF DESCRIPTION OF THE FIGURES [0011] Figures 1a, 1b, and 1c comprise three graphs showing the conversion of tetrabenazine, compound 2-1 and compound 20 3-1 to their respective metabolites in human hepatocytes. Figures 2a - 2f comprise six graphs showing the stability profile of compounds 3-1 and 2-1 in rat, dog and human liver microsomes. Figures 3a - 3d comprise four graphs showing the pharmacokinetic properties of compounds 2-1 and 3-1 in dogs and rats and of 1d.1 in the rat. 25 DETAILED DESCRIPTION OF THE INVENTION [0012] As mentioned above, the present invention is directed generally to substitutedisobutyl- 3- 9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compounds. The compounds of this invention have the follow- 30 ing structure (I): 35 40 and stereoisomers, pharmaceutically acceptable salts and solvates thereof, wherein R1 is -C(=O)-O-alkyl; or wherein R1 is -C(=O)-C1-6alkanediyl-NH2, and wherein said 1-6Calkanediyl is -CH2-; -CH2CH2-, -CH(CH3)-, 45 -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2C(CH3)2CH2- -CH[CH(CH3)2]-, -CHCH2[CH(CH3)2]-, or -C(CH3)2- and is op- tionally substituted with a group selected from -NH- C(=NH)NH2, -CO2H, -CO2Me, -SH, -C(O)NH2, -NH2, -SCH3 phenyl, -OH, 4-hydroxy-phenyl, imidazolyl and indolyl. [0013] As used herein, the above terms have the following meaning: [0014] "alkyl" means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon 50 containing from 1 to 10 carbon atoms, while the term "C 1-4alkyl" has the same meaning as alkyl but contains from 1 to 4 carbon atoms.
Load more

Recommended publications
  • Management of Side Effects of Antipsychotics
    Management of side effects of antipsychotics Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program www.mghcme.org Disclosures I have the following relevant financial relationship with a commercial interest to disclose (recipient SELF; content SCHIZOPHRENIA): • Alkermes – Consultant honoraria (Advisory Board) • Avanir – Research grant (to institution) • Janssen – Research grant (to institution), consultant honoraria (Advisory Board) • Neurocrine – Consultant honoraria (Advisory Board) • Novartis – Consultant honoraria • Otsuka – Research grant (to institution) • Roche – Consultant honoraria • Saladax – Research grant (to institution) • Elsevier – Honoraria (medical editing) • Global Medical Education – Honoraria (CME speaker and content developer) • Medscape – Honoraria (CME speaker) • Wolters-Kluwer – Royalties (content developer) • UpToDate – Royalties, honoraria (content developer and editor) • American Psychiatric Association – Consultant honoraria (SMI Adviser) www.mghcme.org Outline • Antipsychotic side effect summary • Critical side effect management – NMS – Cardiac side effects – Gastrointestinal side effects – Clozapine black box warnings • Routine side effect management – Metabolic side effects – Motor side effects – Prolactin elevation • The man-in-the-arena algorithm www.mghcme.org Receptor profile and side effects • Alpha-1 – Hypotension: slow titration • Dopamine-2 – Dystonia: prophylactic anticholinergic – Akathisia, parkinsonism, tardive dyskinesia – Hyperprolactinemia • Histamine-1 – Sedation – Weight gain
    [Show full text]
  • Drug-Induced Movement Disorders
    Medical Management of Early PD Samer D. Tabbal, M.D. May 2016 Associate Professor of Neurology Director of The Parkinson Disease & Other Movement Disorders Program Mobile: +961 70 65 89 85 email: [email protected] Conflict of Interest Statement No drug company pays me any money Outline So, you diagnosed Parkinson disease .Natural history of the disease .When to start drug therapy? .Which drug to use first for symptomatic treatment? ● Levodopa vs dopamine agonist vs MAOI Natural History of Parkinson Disease Before levodopa: Death within 10 years After levodopa: . “Honeymoon” period (~ 5-7 years) . Motor (ON/OFF) fluctuations & dyskinesias: ● Drug therapy effective initially ● Surgical intervention by 10-15 years - Deep brain stimulation (DBS) therapy Motor Response Dyskinesia 5-7 yrs >10 yrs Dyskinesia ON state ON state OFF state OFF state time time Several days Several hours 1-2 hour Natural History of Parkinson Disease Prominent gait impairment and autonomic symptoms by 20-25 years (Merola 2011) Behavioral changes before or with motor symptoms: . Sleep disorders . Depression . Anxiety . Hallucinations, paranoid delusions Dementia at anytime during the illness . When prominent or early: diffuse Lewy body disease Symptoms of Parkinson Disease Motor Symptoms Sensory Symptoms Mental Symptoms: . Cognitive and psychiatric Autonomic Symptoms Presenting Symptoms of Parkinson Disease Mood disorders: depression and lack of motivation Sleep disorders: “acting out dreams” and nightmares Early motor symptoms: Typically Unilateral . Rest tremor: chin, arms or legs or “inner tremor” . Bradykinesia: focal and generalized slowness . Rigidity: “muscle stiffness or ache” Also: (usually no early postural instability) . Facial masking with hypophonia: “does not smile anymore” or “looks unhappy all the time” .
    [Show full text]
  • 2009 Paris, France the Movement Disorder Society’S 13Th International Congress of Parkinson’S Disease and Movement Disorders
    FINAL PROGRAM The Movement Disorder Society’s 13th International Congress OF PARKINSon’S DISEASE AND MOVEMENT DISORDERS JUNE 7-11, 2009 Paris, France The Movement Disorder Society’s 13th International Congress of Parkinson’s Disease and Movement Disorders Claiming CME Credit To claim CME credit for your participation in the MDS 13th International Congress of Parkinson’s Disease and Movement Disorders, International Congress participants must complete and submit an online CME Request Form. This Form will be available beginning June 10. Instructions for claiming credit: • After June 10, visit www.movementdisorders.org/congress/congress09/cme • Log in following the instructions on the page. You will need your International Congress Reference Number, located on the upper right of the Confirmation Sheet found in your registration packet. • Follow the on-screen instructions to claim CME Credit for the sessions you attended. • You may print your certificate from your home or office, or save it as a PDF for your records. Continuing Medical Education The Movement Disorder Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation The Movement Disorder Society designates this educational activity for a maximum of 30.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Non-CME Certificates of Attendance were included with your on- site registration packet. If you did not receive one, please e-mail [email protected] to request one. The Movement Disorder Society has sought accreditation from the European Accreditation Council for Continuing Medical Education (EACCME) to provide the following CME activity for medical specialists.
    [Show full text]
  • Tetrabenazine: the First Approved Drug for the Treatment of Chorea in US Patients with Huntington Disease
    Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW 7HWUDEHQD]LQHWKHÀUVWDSSURYHGGUXJ for the treatment of chorea in US patients with Huntington disease Samuel Frank Abstract: Huntington disease (HD) is a dominantly inherited progressive neurological disease Boston University School of Medicine, characterized by chorea, an involuntary brief movement that tends to flow between body regions. Boston, Massachusetts, USA HD is typically diagnosed based on clinical findings in the setting of a family history and may be confirmed with genetic testing. Predictive testing is available to those at risk, but only experienced clinicians should perform the counseling and testing. Multiple areas of the brain degenerate mainly involving the neurotransmitters dopamine, glutamate, and G-aminobutyric acid. Although pharmacotherapies theoretically target these neurotransmitters, few well-conducted trials for symptomatic or neuroprotective interventions yielded positive results. Tetrabenazine (TBZ) is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. Some newer antipsychotic agents, such as olanzapine and aripiprazole, may have adequate efficacy with a more favorable adverse-effect profile than older antipsychotic agents for treating chorea and psychosis. This review will address the epidemiology and diagnosis of HD as background for understanding potential pharmacological treatment options. Because TBZ is the only US Food and Drug Administration-approved medication in the United States for HD, the focus of this review will be on its pharmacology, efficacy, safety, and practical uses. There are no current treatments to change the course of HD, but education and symptomatic therapies can be effective tools for clinicians to use with patients and families affected by HD.
    [Show full text]
  • Pathology, Prevention and Therapeutics of Neurodegenerative Disease
    Pathology, Prevention and Therapeutics of Neurodegenerative Disease Sarika Singh Neeraj Joshi Editors 123 Pathology, Prevention and Therapeutics of Neurodegenerative Disease Sarika Singh • Neeraj Joshi Editors Pathology, Prevention and Therapeutics of Neurodegenerative Disease Editors Sarika Singh Neeraj Joshi Toxicology and Experimental Department of Surgery Medicine Division Samuel Oschin Comprehensive Cancer CSIR-Central Drug Research Institute Institute, Cedar Sinai Medical Center Lucknow Los Angeles, CA India USA ISBN 978-981-13-0943-4 ISBN 978-981-13-0944-1 (eBook) https://doi.org/10.1007/978-981-13-0944-1 Library of Congress Control Number: 2018952338 © Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.
    [Show full text]
  • Clinical Study Protocol with Amendment 3 an Open-Label
    Clinical Study Protocol with Amendment 3 An Open-Label, Long Term Safety Study of SD-809 ER in Subjects with Chorea Associated with Huntington Disease Study SD-809-C-16 NCT01897896 Protocol with Amendment 3 Approval Date: 2 March 2015 &21),'(17,$/ 7KHIROORZLQJFRQWDLQVFRQILGHQWLDOSURSULHWDU\LQIRUPDWLRQZKLFKLVWKHSURSHUW\RI $XVSH[3KDUPDFHXWLFDOV,QF 35272&2/180%(56'& $123(1/$%(//21*7(506$)(7<678'<2)6'(5,1 68%-(&76:,7+&+25($$662&,$7(':,7+ +817,1*721',6($6( $OWHUQDWLYHVIRU5HGXFLQJ&KRUHDLQ+XQWLQJWRQ'LVHDVH $5&+' 0DUFK $PHQGPHQW 'HYHORSPHQW3KDVH Auspex Pharmaceuticals, Inc. Protocol SD-809-C-16 Huntington Study Group ARC-HD STUDY CONTACTS SPONSOR: Auspex Pharmaceuticals, Inc. 3333 N. Torrey Pines Court, Suite 400 La Jolla, CA 92037 USA Principal Investigator Co-Principal Investigator CLINICAL MONITOR Amendment 3 CONFIDENTIAL 2 Auspex Pharmaceuticals, Inc. Protocol SD-809-C-16 Huntington Study Group ARC-HD PROTOCOL SYNOPSIS PROTOCOL SD-809-C-16 TITLE An Open-Label, Long Term Safety Study of SD-809 ER in Subjects With Chorea Associated With Huntington Disease Running Title Alternatives for Reducing Chorea in HD (ARC-HD) PHASE 3 (Safety) INDICATION Treatment of chorea associated with Huntington disease NO. SITES Approximately 40 OBJECTIVES 1) Evaluate the safety and tolerability of titration and maintenance therapy with SD-809 ER 2) Evaluate the safety and tolerability of switching subjects from tetrabenazine to SD-809 ER 3) Evaluate the pharmacokinetics of tetrabenazine, SD-809 and their respective α- and β-HTBZ metabolites in subjects switching from tetrabenazine to SD-809 ER STUDY Approximately 116 male and female adult subjects with manifest Huntington disease POPULATION (HD) who are receiving approved doses of tetrabenazine for treatment of chorea (approx.
    [Show full text]
  • Metabolic Enzyme/Protease
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Metabolic Enzyme/Protease Metabolic pathways are enzyme-mediated biochemical reactions that lead to biosynthesis (anabolism) or breakdown (catabolism) of natural product small molecules within a cell or tissue. In each pathway, enzymes catalyze the conversion of substrates into structurally similar products. Metabolic processes typically transform small molecules, but also include macromolecular processes such as DNA repair and replication, and protein synthesis and degradation. Metabolism maintains the living state of the cells and the organism. Proteases are used throughout an organism for various metabolic processes. Proteases control a great variety of physiological processes that are critical for life, including the immune response, cell cycle, cell death, wound healing, food digestion, and protein and organelle recycling. On the basis of the type of the key amino acid in the active site of the protease and the mechanism of peptide bond cleavage, proteases can be classified into six groups: cysteine, serine, threonine, glutamic acid, aspartate proteases, as well as matrix metalloproteases. Proteases can not only activate proteins such as cytokines, or inactivate them such as numerous repair proteins during apoptosis, but also expose cryptic sites, such as occurs with β-secretase during amyloid precursor protein processing, shed various transmembrane proteins such as occurs with metalloproteases and cysteine proteases, or convert receptor agonists into antagonists and vice versa such as chemokine conversions carried out by metalloproteases, dipeptidyl peptidase IV and some cathepsins. In addition to the catalytic domains, a great number of proteases contain numerous additional domains or modules that substantially increase the complexity of their functions.
    [Show full text]
  • In Vivo Imaging of Endogenous Pancreatic B-Cell Mass in Healthy and Type 1 Diabetic Subjects Using 18F-Fluoropropyl-Dihydrotetrabenazine and PET
    In Vivo Imaging of Endogenous Pancreatic b-Cell Mass in Healthy and Type 1 Diabetic Subjects Using 18F-Fluoropropyl-Dihydrotetrabenazine and PET Marc D. Normandin1, Kitt F. Petersen2, Yu-Shin Ding1, Shu-Fei Lin1, Sarita Naik2,KristaFowles1, Daniel M. Skovronsky3, Kevan C. Herold4, Timothy J. McCarthy5,RobertoA.Calle5,RichardE.Carson1, Judith L. Treadway5, andGaryW.Cline2 1Department of Diagnostic Radiology, Yale University, New Haven, Connecticut; 2Department of Endocrinology, Yale University, New Haven, Connecticut; 3Avid Radiopharmaceuticals, Philadelphia, Pennsylvania; 4Department of Immunobiology, Yale University, New Haven, Connecticut; and 5Pfizer Global R&D, Groton, Connecticut Key Words: diabetes; pancreas; beta cell mass; PET The ability to noninvasively measure endogenous pancreatic J Nucl Med 2012; 53:908–916 b-cell mass (BCM) would accelerate research on the pathophys- DOI: 10.2967/jnumed.111.100545 iology of diabetes and revolutionize the preclinical development of new treatments, the clinical assessment of therapeutic effi- cacy, and the early diagnosis and subsequent monitoring of dis- ease progression. The vesicular monoamine transporter type 2 (VMAT2) is coexpressed with insulin in b-cells and represents a promising target for BCM imaging. Methods: We evaluated The lack of robust methods for noninvasive imaging of the VMAT2 radiotracer 18F-fluoropropyl-dihydrotetrabenazine endogenous pancreatic islet b-cell mass (BCM) hampers 18 18 ( F-FP-(1)-DTBZ, also known as F-AV-133) for quantitative the development of treatments to prevent or reverse the loss PET of BCM in healthy control subjects and patients with type 1 of BCM in type 1 diabetes mellitus (T1DM). Strategies for diabetes mellitus. Standardized uptake value was calculated as the net tracer uptake in the pancreas normalized by injected imaging BCM by PET and SPECT using radiotracers tar- dose and body weight.
    [Show full text]
  • Movement Disorders Therapeutic Class Review (TCR)
    Movement Disorders Therapeutic Class Review (TCR) April 3, 2020 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. Movement
    [Show full text]
  • Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine
    Drugs R D (2017) 17:449–459 DOI 10.1007/s40268-017-0202-z ORIGINAL RESEARCH ARTICLE Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine 1 1 1 1 Heather Skor • Evan B. Smith • Gordon Loewen • Christopher F. O’Brien • 1 1 Dimitri E. Grigoriadis • Haig Bozigian Published online: 3 August 2017 Ó The Author(s) 2017. This article is an open access publication Abstract generally held assertion that [?]-a-HTBZ is the major Background Tetrabenazine (TBZ) activity is thought to contributor. [-]-a-HTBZ, the other abundant TBZ result from four isomeric dihydrotetrabenazine (HTBZ) metabolite, has much lower VMAT2 inhibitory potency metabolites ([?]-a-HTBZ, [-]-a-HTBZ, [?]-b-HTBZ, than [?]-b-HTBZ, but increased affinity for other CNS [-]-b-HTBZ). Each isomer has a unique profile of vesic- targets, which may contribute to off-target effects of TBZ. ular monoamine transporter 2 (VMAT2) inhibition and off- In contrast, pharmacological activity for VBZ is derived target binding. Previously published data only report total primarily from [?]-a-HTBZ. Individual HTBZ isomer isomer (a) and (b) concentrations. We developed a method concentrations provide a more clinically relevant endpoint to quantify the individual HTBZ isomers in samples from for assessing on- and off-target effects of TBZ than total patients with Huntington’s disease receiving TBZ. For isomer concentrations. comparison, concentrations of [?]-a-HTBZ, the single active metabolite shared by valbenazine (VBZ) and TBZ, were determined in samples from patients with tardive Key Points dyskinesia receiving VBZ. Methods A liquid chromatography–tandem mass spec- This study presents the first reported method for trometry (LC-MS/MS) method was developed and vali- quantifying the four different isomeric dated for quantitation of the four individual HTBZ isomers.
    [Show full text]
  • Imaging the Neurochemistry of Alcohol and Substance Abuse
    539 NEUROIMAGING CLINICS OF NORTH AMERICA Neuroimag Clin N Am 17 (2007) 539–555 Imaging the Neurochemistry of Alcohol and Substance Abuse Diana Martinez, MDa,*, Jong-Hoon Kim, MDa, John Krystal, MDb, Anissa Abi-Dargham, MDa,c - Cocaine dependence Behavioral correlates of low D2/3 receptor Dopamine D2/3 receptors and dopamine binding potential transmission Alcohol dependence and presynaptic Functional significance of low D2/3 dopamine receptor binding in cocaine Alcohol dependence and the dopamine dependence transporter Behavior and dopamine transmission Serotonin and alcohol dependence Imaging cue-induced craving in cocaine Measures of GABA in alcohol dependence dependence Opioids and alcohol dependence Cocaine dependence and the dopamine - Heroin dependence transporter - Methamphetamine abuse Imaging studies of cocaine dependence - Methylenedioxymethamphetamine and other neurotransmitters (Ecstasy) abuse - Alcohol dependence - Hallucinogens - Dopamine D2/3 receptor and alcohol Summary dependence - References Positron emission tomography (PET) and single we briefly overview the concepts that are needed photon emission computed tomography (SPECT) to interpret these studies. The PET radiotracers use radiotracers to image molecular targets in the most frequently used in substance abuse research human brain. These techniques have been applied are those that label the dopamine type 2/3 (D2/3) over the last decade to study addiction and provide receptors of the striatum, such as the antagonists an important body of knowledge about the neuro-
    [Show full text]
  • Physician-Related Services/Health Care Professional Services Billing Guide
    Washington Apple Health (Medicaid) Physician-Related Services/Health Care Professional Services May 6, 2021 Disclaimer Every effort has been made to ensure this guide’s accuracy. If an actual or apparent conflict between this document and a Health Care Authority (HCA) rule arises, HCA rules apply. Billing guides are updated on a regular basis. Due to the nature of content change on the internet, we do not fix broken links in past guides. If you find a broken link, please check the most recent version of the guide. If this is the most recent guide, please notify us at [email protected]. About this guide1 This publication takes effective May 6, 2021 and supersedes earlier billing guides to this program. Unless otherwise specified, the program(s) in this guide is governed by the rules found in Chapter 182-531 WAC. HCA is committed to providing equal access to our services. If you need an accommodation or require documents in another format, please call 1-800-562- 3022. People who have hearing or speech disabilities, please call 711 for relay services. Washington Apple Health means the public health insurance programs for eligible Washington residents. Washington Apple Health is the name used in Washington State for Medicaid, the children’s health insurance program (CHIP), and state-only funded health care programs. Washington Apple Health is administered by the Washington State Health Care Authority. Refer also to HCA’s ProviderOne billing and resource guide for valuable information to help you conduct business with the Health Care Authority. 1 This publication is a billing instruction.
    [Show full text]