Novel Positron Emission Tomography (PET) Radiotracer to Image Phosphodiesterase-4B (PDE4B)

Objective:

Phosphodiesterase type 4 (PDE4) terminates signal transduction of guanine nucleotidebinding
proteins (G-protein)-coupled receptors by metabolizing the second messenger 3 <=,5 <=- cyclic
adenosine monophosphate (cAMP). PDE4 is selective to cAMP over cyclic guanosine
monophosphate. PDE4 has four isozymes A, B, C, and D and basic studies indicate that type B
(PDE4B) plays a key role in cognitive function and neuroinflammation. Thus, PDE4B inhibitors
would be expected to improve cognitive function and have anti-inflammatory effects. Pfizer
has developed a new PET ligand, 18F-PF-06445974, to selectively image PDE4B; the ligand has
shown promising results in non-human primates.

This protocol covers four phases:

1. Phase 1: whole body imaging of one subject with a low injection activity of 2 mCi to
confirm that no organ has prominently high uptake of 18F-PF-06445974;

2. Phase 2: kinetic brain imaging with up to 5 mCi injection to quantify PDE4B in brain
relative to concurrent measurement of the parent radioligand in arterial plasma;

3. Phase 3: if 18F-PF-06445974 is successful in Phase 2 in the first couple of subjects, we
will estimate the radiation-absorbed doses by performing whole body imaging with 5 mCi
injection;

4. Phase 4: test-retest analysis of brain binding relative to concurrent measurement of the
parent radioligand in arterial plasma (5 mCi per scan).

Study Population:

Healthy adult female and male volunteers (n=22, ages 18 or older) will undergo brain imaging.
An additional eight healthy volunteers will undergo whole body dosimetry analysis, for a
total of 30 healthy volunteers.

Design:

For quantification of 18F-PF-06445974, 22 healthy controls will undergo brain PET imaging
using 18F-PF-06445974 and an arterial line. Some of them will have a test-retest scan. Eight
additional subjects will have a whole body PET scan for dosimetry. For dosimetry, no arterial
line will be used.

Outcome Measures:

To assess quantitation of PDE4B with 18F-PF-06445974, we will primarily use two outcome
measures, namely the identifiability and time stability of distribution volume (VT)
calculated with compartmental modeling. In the test-retest study, we will calculate the
retest

variability. We will assess whole-body biodistribution and dosimetry of 18F-PF-06445974 by
calculating doses to organs and effective dose to the body.

- INCLUSION CRITERIA:

- Age 18 or older.

- 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).

EXCLUSION CRITERIA:

- Any current Axis I diagnosis.

- Clinically significant laboratory abnormalities

- Positive HIV test.

- Unable to have an MRI scan.

- History of neurologic illness or injury with the potential to affect study data
interpretation.

- Recent exposure to radiation related to research (i.e. 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.

- Current substance use disorder based on DSM-5.

- Current use of psychiatric medications.

- NIMH employees/staff and their immediate family members will be excluded from the
study per NIMH policy.

Exclusion criteria for the dosimetry subjects are the same as reported above, with the
exception of MRI contraindications, because an MRI will not be performed in these subjects.