Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm

This biomechanistic GABA-A receptor target engagement study includes clinical and motor
assessments before and at various time points up to approximately 90 minutes after the i.v.
administration of 1 mg flumazenil and placebo in Parkinson disease subjects. Thirty Parkinson
disease subjects with disease severity (Hoehn and Yahr) stages 2-4 will be recruited.
Baseline [11C]FMZ and vesicular monoamine transporter type 2 (VMAT2) [11C]DTBZ brain PET
imaging will be performed prior to drug administration to assess for GABA-A receptor
availability and the integrity of nigrostriatal dopaminergic nerve terminals, respectively.

Inclusion Criteria:

1. Parkinson's disease (PD): PD diagnosis will follow the UK Parkinson's Disease Society
Brain Bank Research Center (UKPDSBRC) clinical diagnostic criteria for PD.

2. Hoehn and Yahr stages 2-4

3. Absence of dementia confirmed by cognitive testing.

4. Abnormal 11C-Dihydrotetrabenazine ([11C]-DTBZ) PET study to demonstrate nigrostriatal
dopaminergic denervation.

Exclusion Criteria:

1. PD with Dementia (PDD) or dementia with Lewy bodies (DLB).

2. Other disorders which may resemble PD, such as vascular dementia, normal pressure
hydrocephalus, multiple system atrophy, corticobasal ganglionic degeneration, or toxic
causes of parkinsonism. Prototypical cases have distinctive clinical profiles, like
early and severe dysautonomia or appendicular apraxia, which may differentiate them
from idiopathic PD. The use of the UKPDSBRC clinical diagnostic criteria for PD will
mitigate the inclusion of subjects with atypical parkinsonism.

3. Subjects on benzodiazepine, GABA-ergic medications (baclofen, tizanidine),
neuroleptic, anticholinergic (trihexyphenidyl, benztropine), or cholinesterase
inhibitor drugs.

4. Evidence of a mass lesion on structural brain imaging (MRI).

5. Participants in whom MRI is contraindicated including, but not limited to, those with
a pacemaker, presence of metallic fragments near the eyes or spinal cord, chest, or
cochlear implant.

6. Severe claustrophobia precluding MR or PET imaging.

7. Subjects limited by participation in research procedures involving ionizing radiation.

8. Pregnancy (urine or serum pregnancy test within 48 hours of each PET session) or
breastfeeding.

9. History of seizures

10. Significant anxiety or history of panic disorder.

11. History of recent suicide attempt or overdose of tricyclic antidepressants or other
medications

12. Any other medical history determined by investigators to preclude safe participation.

13. Allergy to flumazenil

14. Significant liver disease

15. History of alcohol or other substance abuse within past two years.

16. History of regular benzodiazepine use within past year