Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [11C]Flumazenil PET

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 [11C]flumazenil positron emission tomography (PET) in primates and ex vivo [3H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the Kd 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. Thes...