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.