Abstract Parkinson’s Disease (PD) is a neurodegenerative disorder that affects over 1 million U.S. citizens. PD is most often diagnosed in people over the age of 60, while only 4% of cases of PD are diagnosed before age 50, making age the biggest risk factor for the development of PD. The four cardinal features of PD include tremor, rigidity, bradykinesia, and postural instability, often associated with non-motor symptoms including depression, anxiety, sleep behavior disorders, constipation, loss of sense of smell, and cognitive impairment. The most prominent PD pathology is degeneration of dopaminergic neurons in the ventrolateral tier of the pars compacta of the substantia nigra in the midbrain and the formation of α-synuclein cytoplasmic inclusions throughout the brain. While current medical therapies for PD significantly improve the quality of life of PD patients, none of these therapies has been convincingly shown to slow or prevent the progression of PD, requiring the development of treatments that can provide greater neuroprotection. To address these issues, Entobee Therapeutics proposes to repurpose N-acetylcysteine (NAC), a well-studied, safe, FDA-approved drug, to manage PD. Given the pathogenetic role of oxidative damage in PD, Entobee hypothesizes that targeted antioxidant intervention with NAC may reduce or halt the progressive dopaminergic neurodegeneration associated with PD. However, the administration of NAC has limitations in both intravenous and oral forms. Thus, Entobee proposes the creation of a novel intranasal (IN) nose-to-brain (N2B) treatment option to bypass first-pass hepatic gastrointestinal metabolism and the blood-brain barrier (BBB) for faster outpatient and simple chronic care. The overall objective of this Phase I project is to identify a safe IN N2B dose of NAC with equivalent or better brain bioavailability compared to the 50 mg/kg i.v. NAC dose associated with dopaminergic improvement in PD patients using magnetic resonance spectroscopy to measure NAC-derived GSH in disease-relevant regions of the brain. This will be accomplished through the following aims: 1) Establish the regional (striatum, midbrain, and cortex) and temporal (1–6 h and 24 h) single-dose bioavailability profile of 50 mg/kg i.v. NAC in PD patients, 2) Compare the single-dose bioavailability and safety profiles of 200 mg and 400 mg IN N2B NAC versus 50 mg/kg i.v. NAC bioavailability profile in PD patients, 3) Confirm the single-dose safety and tolerability of an equally bioavailable IN N2B NAC dose in PD patients.