Abstract
Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has four isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand 18F-PF-06445974 in the brains of rodents, monkeys, and humans. Methods: Three monkeys and five healthy human volunteers underwent positron emission tomography (PET) scans after intravenous injection of 18F-PF-06445974. Brain uptake was quantified as total distribution volume (VT) using the standard two-tissue compartment model and serial concentrations of parent radioligand in arterial plasma. Results: 18F-PF-06445974 readily distributed throughout monkey and human brain and had highest binding in the thalamus. The value of VT was well identified by a two-tissue compartment model but increased by 10% during the terminal portions (40 and 60 minutes) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. The average human VT values for the whole brain were 9.5 ± 2.4 mL · cm-3. Radiochromatographic analyses in knockout mice showed that two efflux transporters—permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)—completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggest that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Conclusion: 18F-PF-06445974 quantified PDE4B in human brain with reasonable, but not complete, success. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. Because the radiometabolite-induced error was only about 10%, the radioligand is, in the opinion of the authors, suitable to extend to clinical studies.
- Molecular Imaging
- PET
- PET/MRI
- 18F-PF-06445974
- phosphodiesterase-4B (PDE4B)
- positron emission tomography (PET)
- Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging, Inc.