title: Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.
abstract: Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States; The Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Peter J H
authors: PJ
authors: Scott
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Xia
authors: X
authors: Shao
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Timothy J
authors: TJ
authors: Desmond
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Brian G
authors: BG
authors: Hockley
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Phillip
authors: P
authors: Sherman
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Carole A
authors: CA
authors: Quesada
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States; Department of Neurology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
authors: Kirk A
authors: KA
authors: Frey
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Robert A
authors: RA
authors: Koeppe
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors: Michael R
authors: MR
authors: Kilbourn
authors: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States; Department of Neurology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States; Neurology Service and Geriatrics Research, Education, and Clinical Center, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan United States.
authors: Nicolaas I
authors: NI
authors: Bohnen
keywords: Hypersomnia; Parkinson’s disease; [11C]FMZ; positron emission tomography