Subject has a history of clinically significant hypotensive disorder, systolic blood pressure less than or equal to 80 mmHg or a diastolic blood pressure less than or equal to 40 mmHG at any measurement prior to dosing on Day 1, or any clinically significant symptoms associated with hypotension at any time during participation prior to dosing on day 1.
7. Female subject who is pregnant or lactating.
8 Subject has a presence or history of a medically diagnosed, clinically significant psychiatric disorder (including intellectual disability, major depressive disorder with psychosis, and bipolar disorder) other than schizophrenia (medically diagnosed schizoaffective disorder or schizophreniform disorder will be allowed).
9. Subject tests positive for drugs of abuse at screening, however, a positive test for barbiturates, opiates, benzodiazepines or methadone may not result in exclusion of subjects if the Investigator determines that the positive test is as a result of prescription medicine(s). In the event a subject tests positive cannabinoids (tetrahydrocannabinol), the Investigator will evaluate the subject's ability to abstain from using this substance during the study. This information will be discussed with the Medical Monitor prior to study enrollment.
10. Subject is at significant risk of harming him/herself or others according to the Investigator's judgment.
11. Subject has attempted suicide within 6 months prior to screening.
12. Subject is involuntarily hospitalized.
13. Subject is judged in the opinion of the Investigator to be severely resistant to antipsychotic treatment defined as a failure to respond to 4 or more marketed antipsychotic agents, given at an adequate dose as per labeling and for an adequate duration (lifetime).
14. Subject is receiving an antipsychotic medication at a dose above the maximum labeled dose (country-specific) dose at or during the 3 for less than 12 weeks prior to the PET scan at the screening visit
15. Subject has received clozapine treatment within 120 days of planned PET scan at screening.
16. Subject has received electroconvulsive therapy treatment within the 3 months prior to screening or is expected to require ECT during the study.
17. Subject has a history of allergy or hypersensitivity to more than 2 distinct chemical classes of drug (eg, sulfonylureas and penicillins) allergic reaction to any medication or has a known or suspected sensitivity to any substance that is contained in the study drug formulation or to carbidopa or entacapone.
18. Subject has any clinically significant abnormal laboratory values as determined by the Investigator (hematology, serum chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, and serum prolactin). (Note: abnormal findings of questionable significance will be discussed with the Medical Monitor prior to including subject).
19. Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation. Note: Subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 3 times the upper limit of the reference ranges provided by the laboratory require retesting. If on retesting, the laboratory value remains ≥ 3 times the upper limit, the subject will be excluded.
Note: subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) greater than or equal to 3 times the uper limit of the reference ranges provided by the laboratory require retesting. If on retesting, the laboratory value remains greater than or equal to 3 times the upper limit, the subject will be excluded.
20. Subject has bilirubin greater than or equal to 1.5 x upper limit of normal (ULN) with the exception that isolated bilirubin greater than 1.5 x ULN is acceptable if bilirubin is fractioned and direct bilirubin less than 35% at screening.
21. Subject has a serum blood urea nitrogen (BUN) or serum creatinine (Cr) value ≥ 1.5 times the upper limit of normal for the reference range.
22. Subject has experienced significant blood loss (≥ 473 mL), has donated blood within 60 days prior to first dose of study drug, has donated plasma within 72 hours prior to the first dose of study drug or intends to donate plasma or blood or undergo elective surgery during study participation or within 60 days after the last study visit.
23. Subject consumes more than 300 mg of caffeine per day (5 cups of coffee or equivalent in caffeinated beverages).
24. Subject has used disallowed prescription or disallowed nonprescription drugs, or dietary or herbal supplements as specified within the Concomitant Medications and Restrictions for at least 5 half-lives or 14 days prior to dosing, whichever is longer, or anticipates the need for any disallowed medication during their participation in this study (exception: female subjects who are taking oral, patch, or intrauterine device [IUD] hormonal contraceptives, or progestin implant or injection).
25. Subject is a staff member or the relative of a staff member.
26. Subject is in the opinion of the Investigator, unsuitable in any other way to participate in this study.
27. Subject has contraindications to undergoing MRI/fMRI examination including, but not limited to claustrophobia, metal foreign bodies or implanted devices incompatible with the MRI/fMRI exposure.