This is a randomized, placebo-controlled, single ascending dose (SAD) study of SER-252 in participants with Parkinson's Disease (PD) and motor fluctuations.

Participants will be enrolled into five sequential groups. Each group will include eight participants, dosed in a 3:1 ratio (six receiving SER-252 and two receiving placebo). All participants will receive a single dose of study drug. Each successive group will receive a higher dose level of SER-252 than the previous group. Some participants will receive a subcutaneous injection of SER-252, while others will receive placebo.

Single ascending dose (SAD) cohorts will utilize a sentinel dosing approach, with subsequent dosing conducted in a staggered manner if ongoing safety and tolerability assessments allow. In each cohort, the first two participants (one receiving SER-252 and one receiving placebo) will be dosed separately ahead of the remaining participants. These sentinel participants will be observed and evaluated as described in the protocol before dosing proceeds for the rest of the cohort.

Inclusion criteria

1. Female or male participants 40-80 years of age, inclusive, at the time of screening
2. Diagnosis of idiopathic Parkinson's disease consistent with UK Brain Bank and MDS Research Criteria; must include bradykinesia with sequence effect, motor asymmetry if no rest tremor, and a reliable, visible response to levodopa
3. On a stable regimen of anti-Parkinsonian medication for at least 4 weeks prior to Screening; MAOBIs must be stable for at least 12 weeks prior to Screening
4. Routine early-morning OFF, corroborated by investigator interview at Screening
5. Presence of a total daily OFF time duration of ≥2 hours during the waking day based on participant self-assessment and Investigator's judgment
6. *Hoehn and Yahr scale ≤ 3 in the ON state during screening (*part of the MDS- UPDRS Part III assessment)
7. Levodopa administration at least 4 times daily (immediate or extended release) or three times daily (Rytary or Crexont)
8. Ability to return to the clinic for blood sampling, clinical and laboratory assessment on scheduled days, based upon cohort
9. Montreal Cognitive Assessment ≥ 24
10. Women of child-bearing potential (WOCBP) who are sexually active with a male partner must use a reliable method of contraception from the time of consent through at least 3 months after the last dose of study medication. Reliable methods of contraception include oral contraceptive or long-term injectable or implantable hormonal contraceptive, or intra-uterine devices when used in combination with male condoms, and must have a negative serum pregnancy test at Screening and negative urine pregnancy test at baseline. Males who are sexually active and whose partners are females of childbearing potential must agree to use male condoms from the time of consent through 3 months after administration of the last dose of study drug, and their partners must be willing to use a highly effective method of contraception from screening through 3 months after administration of the last dose of study drug.
11. Willing and able to comply with all study activities and requirements, including safety follow-up
12. Provide written informed consent
13. Approved by a central Enrollment Authorization Committee (EAC)

Exclusion criteria

1. Diagnosis of secondary or atypical parkinsonism

2. Any previous procedure or therapy designed to provide continuous levodopa or stimulation of dopaminergic tone (i.e., Duopa, apomorphine), surgery for PD (i.e., DBS), or anticipation of these during the study

3. History of exclusively diphasic, OFF state, myoclonic or dystonic dyskinesias without peak-dose choreiform dyskinesia

4. Clinically debilitating motor complications as determined by the principal investigator or delegate (severe, disabling dyskinesias or severe OFF)

5. Participant inability to differentiate motor states (OFF/ON/ON with mild/moderate/severe dyskinesias) after training

6. Clinically significant orthostatic hypotension (consistently symptomatic or requires medication)

7. Clinically significant hallucinations requiring antipsychotic use

8. Clinically significant medical, surgical, psychiatric, or laboratory abnormalities that in the judgment of the principal investigator or delegate would preclude adequate participation or completion of the study

9. Clinically significant ECG abnormalities at Screening

10. Prolonged Fridericia-corrected QT (QTcF) interval on ECG at Screening (defined as a QTcF interval of >450 msec for males and 470 for females)

11. Clinically significant heart disease within 2 years of Screening, defined as follows:

    A. Significant cardiac event within 12 weeks prior to Screening (e.g., admission for myocardial infarction, unstable angina, or decompensated heart failure), angina pectoris or episode of congestive heart failure with symptoms > grade 2 New York Heart Association classification, or presence of cardiac disease that in the opinion of the investigator increases the risk of ventricular arrhythmia B. History of complex arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia) that was symptomatic or required treatment (Common Terminology Criteria for Adverse Events grade 3) C. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia D. Symptomatic bradycardia, sick sinus syndrome or atrioventricular block greater than first degree in the absence of a pacemaker E. Unexplained syncope F. Brugada syndrome G. Hypertrophic cardiomyopathy

12. Active major depressive disorder or history of clinically significant impulse control disorder, in the opinion of the Principal Investigator or delegate, or EAC.

    Note: Participants receiving treatment for depression with antidepressants may be enrolled if they have been on a stable daily dose of the antidepressant for at least 8 weeks prior to Screening.

13. Has active suicidal ideation within one year prior to Screening as determined by the C-SSRS (answer of "yes" on questions 4 or 5) or attempted suicide within the last 5 years

14. Has been diagnosed with or history of a substance-related disorder (excluding nicotine and caffeine), including alcohol-related disorder by DSM-V criteria, during the 12 months prior to Screening

15. Tests positive at Screening for drugs of abuse (amphetamines (AMP), barbiturates (BAR), benzodiazepines (BZO), cocaine (COC), opiates (OPI), methamphetamines (MET), methadone (MTD), Phencyclidine (PCP), tetrahydrocannabinol (THC), tricyclic antidepressants (TCA)) Note: does not exclude patients on physician-prescribed medications.

16. Has ALT or AST levels greater than 2.5 times the ULN or bilirubin > 2.0 mg/dL, or > 34.2 µmol/L

17. Significant renal impairment as determined by eGFR, using Cockcroft-Gault method, less than or equal to 55 ml/min or serum creatinine >2.0 mg/dL or >177 µmol/L

18. Has a positive test result for HBsAg, HCV antibody, or HIV infection at Screening

19. Currently lactating or pregnant or planning to become pregnant during the study.

20. Previous intolerance of apomorphine

21. Currently participating in or has participated in another investigational study within the last 30 days or 5 half-lives, or 90 days for biologics