Abstract
241480
Introduction: Phosphodiesterase 4 (PDE4) terminates cyclic adenosine monophosphate (cAMP) signaling. Inhibition of PDE4B in particular has been shown to have antidepressant-like effects in animals and anti-inflammatory effects in human disorders (e.g., psoriasis and chronic obstructive pulmonary disease). We developed [18F]PF-06445974 (PF974) as a radioligand that preferentially binds to PDE4B to study cAMP signaling in humans and animals and as a potential biomarker of neuroinflammation. The purpose of the current study was to determine specificity of PF974 for PDE4B, as well as to determine the effects of an inflammatory stimulus on PF974 binding in comparison to TSPO, the current gold-standard in inflammatory imaging.
Methods: Ten male wild-type Sprague-Dawley rats were injected with LPS in unilateral striatum and were imaged with either PF974 or ER176, both 24 hours and eight days after injection. Rat brains were collected after tracer injection, and radiometabolite studies were performed using high-performance liquid chromatography (HPLC). Displacement studies were performed with IV rolipram, a PDE4 inhibitor, at 1 mg/kg, and pre-block studies were performed with PF974 at 0.4 mg/kg.
Results: At Day 1 after LPS injection, binding of PF974 in the LPS-injected striatum increased about 50% compared to the contralateral region, a difference that disappeared at Day 8 post-injection. In contrast, the translocator protein 18kDa (TSPO) ligand ER176 showed no significant separation at Day 1, but a difference was clearly noted at Day 8. Ex vivo measurements demonstrated that the increased uptake was overwhelmingly due to increase in parent radioligand binding with only minor leakage of plasma radiometabolites. Rolipram displaced PF974 binding one hour post-injection, while cold carrier PF974 abolished uptake in a pre-block paradigm.
Conclusions: We demonstrate here that LPS increased radioligand binding without significant radiometabolite contamination and that PF974 was specific for PDE4B. Local injection of LPS in rat brain increased radioligand uptake without significant contamination of plasma-based radiometabolites, an effect that was transient and associated with active neuroinflammation. In contrast, TSPO uptake remained increased after Day 8, primarily due to parent radioligand. Further, blockade and displacement studies confirmed the specificity of radioligand for PDE4B. This increased binding may be caused by the phosphorylation/activation of PDE4B and suggests that PDE4B imaging with PF974 may function as a dynamic biomarker of neuroinflammation in the brain.
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