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

Depression

Healthy Control Subjects, PET Imaging, Receptor Occupancy, Depression

Background: The brain enzyme phosphodiesterase-4D (PDE4D) may affect thinking and depression. Drugs with some radioactivity can attach to enzymes and be seen on a scan. Researchers want to test a new radioactive drug, 11C-T-1650, to measure PDE4D in the brain and body. They also want to see if the new drug BPN14770 blocks 11C-T-1650 from the brain. They want to learn more about psychiatric disorders and possible treatments. Objectives: To study how well 11C-T-1650 helps show PDE4D on a scan and to see if BPN14770 blocks it. Eligibility: Healthy adults at least 18 years old Design: Participants will be screened in other protocols. Some participants will have 1 body PET scan. Some participants will have 2 brain PET scans and 1 brain MRI within 1 year. Some participants (ages 18 55) will: Have 3 brain PET scans and 1 MRI Take BPN14770 by mouth twice daily for 3 7 days Have blood and urine tests Have a follow-up physical exam and heart test PET (positron emission tomography) scans will take 2 3 hours. Participants will: Have a thin plastic tube (catheter) placed in an arm vein by needle. Get a small amount of 11C-T-1650 injected via catheter. Another catheter may be placed to draw blood. Lie quietly on a bed that slides into a donut-shaped scanner without sleeping. They may get a short break. Have heart and vital signs monitored. Have blood and urine tests. Learn about drinking fluids and urinating after the scan MRI (magnetic resonance imagining) scans will take 30 60 minutes: Participants will lie on a table that slides into a metal cylinder in a magnetic field. Sponsoring Institute: National Institute of Mental Health ...

Objective Phosphodiesterase type 4 (PDE4) metabolizes 3 \<=,5 \<=-cyclic adenosine monophosphate (cAMP), thereby terminating this second messenger. PDE4 is selective to cAMP over cyclic guanosine monophosphate. PDE4 has four isozymes A, B, C, and D and basic studies suggest that type D (PDE4D) may play a key role in cognitive function and depression. That is, PDE4D inhibitors are expected to improve cognitive function and depressive symptoms. In collaboration with Tetra Discovery Partners, we have developed a PET ligand, 11C-T-1650, to selectively image PDE4D. This type D selective ligand was developed based on 3D structural differences between PDE4D and PDE4 type B (PDE4B) Our PET studies using 11C-T-1650 in nonhuman primate have shown promising results, and we now seek to evaluate it in in healthy subjects. This study has three primary objectives. First, we will determine whether the uptake of 11C-T-1650 in the brain reflects the distribution of PDE4D, as demonstrated by blocking with a PDE4D selective compound BPN14770, being developed by Tetra Discovery Partners for treating cognitive disorders including depression. Second, we will measure binding site occupancy of BPN14770 administered at doses that may be used in clinical trials. Third, we will measure the test/retest reproducibility of brain uptake quantified by kinetic modeling and using arterial blood samples. Study Population Healthy adult female and male volunteers (age greater than or equal to 18) will have either brain (n = 30) or whole body imaging (n = 10). Design * Phase 1: We will begin with whole body scanning in a single human subject using up to 10 mCi 11C-T-1650 The aim of this first scan will be to detect a tracer that disproportionately accumulates in a single radiosensitive organ, such as the gonads. If we confirm that radioactivity is fairly widely distributed in the body, higher activities may be injected. * Phase 2: Fifteen healthy subjects will have three brain PET scans using 20 mCi of 11C-T-1650. Scan 1 will serve as the baseline scan for comparison to enzyme occupancy studies (Scan 2 and - Scans 2 and 3 will be enzyme occupancy studies using the PDE4D selective medication BPN14770.Scans 2 and Scan 3 will be performed approximately 90-180 min after the first dose of BPN14770 and after three-day administration, respectively. Scan 3 will be performed approximately 90-180 min after the last dose of the three-day administration of BPN14770. The dose of BPN14770 is 50 mg BID for three days, and a single dose on the fourth day. Comparison between Scan 1 and 2 provides accurate measurement of nonspecific binding of 11C-T-1650. Comparison between Scan 1 and 3 provides enzyme occupancy at a stable plasma concentration of BPN14770 based on Phase 1/2 clinical trials performed by Tetra Discovery Partners. Blood samples will be measured for BPN14770 levels. * Phase 3: To obtain dosimetry information, we will perform a whole body PET scan using 11C-T-1650 (20 mCi) in up to nine healthy subjects. * Phase 4: Fifteen healthy subjects will have two brain PET scans using 20 mCi of 11C-T-1650 to study test/retest reproducibility of the PET measurement. BPN14770 will not be administered in Phases 1, 3 or 4. Outcome Measures For whole body imaging, organ uptake will be quantified as a Standardized Uptake Value (SUV), which normalizes for injected activity and body weight. For Scan 1 and 2 of Phase 2 and all scans of Phase 4, uptake will be quantified as total distribution volume (VT) calculated with kinetic modeling and serial concentrations of parent radioligand in arterial plasma. For Scan 3 of Phase 3, brain uptake (SUV) normalized to plasma concentrations of 11C-T-1650 will be used to measure radioligand binding because the interval between Scan 2 and 3 is too short to repeat placing arterial line. From VT or normalized SUV, occupancy of BPN14770 and nonspecific binding of 11C-T-1650 will be measured. Occupancy of PDE4D will be compared to blood levels of BPN14770.

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