Title: Evaluation of a Novel PET Radioligand for Phosphodiesterase-4D (PDE4D)

• INCLUSION CRITERIA:

All phases

• Age greater than equal 18.
• Able to give written informed consent.
• Medically and psychiatrically healthy.
• Enrolled in 01-M-0254 The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers (PI: Dr. Carlos Zarate) or 17-M-0181 Recruitment and Characterization of Healthy Research Volunteers for NIMH Intramural Studies (PI: Dr. Joyce Chung).

Additional inclusion criterial for Phase 2

• Age less than or equal to 55.
• Body mass index between 18 kg/m2 to 32 kg/m2, inclusive, and body weight of greater than equal 50 kg (110 pounds).
• Female subjects must be surgically sterile (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months prior to dosing of BPN14770), at least two years post-menopausal, or willing to use two barrier methods of contraception from initial screening until one month after taking the last dose of study drug.
• Male subjects must be willing to inform female partners of their participation in the study and must agree to use adequate contraceptive methods (vasectomy performed at least 6 months prior to dosing BPN14770 or use at least one barrier method of birth control).

EXCLUSION CRITERIA

All phases

• Clinically significant laboratory abnormalities based on the following tests (performed under screening protocol 01-M-0254 or 17-M-0181): CBC; acute care panel; hepatic panel; mineral panel; urinalysis; urine drug screen; urine pregnancy test (females); and lipid panel; hepatitis panel (A, B, C); syphilis screening test; total protein; uric acid;creatine kinase; cholesterol; thyroid panel; prothrombin and partial prothrombin tests; and EKG.
• Have a brain disease (such as multiple sclerosis or stroke).
• Any current Axis I diagnosis, based on interview and self-reporting performed under screening protocol 01-M-0254 or 17-M-0181.
• Positive HIV test.
• Current or past history of significant cardiovascular, cerebrovascular, pulmonary, renal, or liver disease. Stable, well-controlled hypertension and hyperlipidemias are allowed.
• Taking psychotropic drugs (i.e. benzodiazepines or antidepressants) including sedative antihistamines; moderate to strong inhibitors or inducers (i.e. fluconazole or ciprofloxacin) of any CYP450 enzyme. A complete listing of such inhibitors or inducers may be found in Attachment 1, List of P450 inhibitors.
• Recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.
• Inability to lie flat on camera bed for at least two hours.
• Pregnancy or breastfeeding.
• Positive screen for drugs of abuse or cotinine (at screen or upon admission), or a positive alcohol result (upon admission).
• Current use of psychiatric medications.
• NIMH employees and staff or immediate family members of NIMH employee/staff.

Additional exclusion criterial for Phase 2 and 4

• coagulation disorder;
• thrombocytopenia;
• Found to have inadequate collateral circulation of the radial artery
• Are unable to have an MRI scan (e.g., pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or shrapnel fragments, metal fragments in the eye)

Additional exclusion criterial for Phase 2

• Marked bradycardia (heart rate 45 beats per minute [bpm]) or tachycardia (heart rate 110 bpm) based on supine ECG values obtained at Screening, before the first dose of BPN14770 on the day of the study. Out-of-range vital signs may be repeated once at each eligibility assessment (prior to the start of dosing).
• History of hematological disorders (e.g., thrombocytopenia) in the immediate family (i.e., parents and siblings).
• Clinically important or significant conduction abnormalities on single ECG