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.

Keywords: Hypersomnia; Parkinson’s disease; [11C]FMZ; positron emission tomography.

Figure 1

Flumazenil (FMZ).

Figure 2

Clarithromycin.

Figure 3

Representative autoradiography images showing high specific binding of [³H]FMZ in the cortex of the rat brain despite increasing concentrations (10 nM, 100 nM, 1 μM, and 10 μM) of clarithromycin.

Figure 4

Representative summed coronal [¹¹C]FMZ PET images from monkey #1 (50–90 min after i.v. injection of the radiotracer) of control animal (A), after displacement with 0.5 mg/kg FMZ (B), and following treatment with 3.5 (C) or 7 mg/kg (D) clarithromycin.

Figure 5

Representative cortical time-radioactivity curves for monkey #1: control study (■), after displacement with 0.5 mg/kg FMZ (□), and following treatment with 3.5 (●) or 7 mg/kg (⧫) clarithromycin.