In vivo imaging of phosphodiesterase IV (PDE4) activity can be quantitatively assessed using the isomers of [11C]rolipram. By imaging both the (+) and (-) isomer and employing blockade studies with aminophylline in normal humans, we will be able to characterize and mathematically model PDE4 activity.
Goal 1: Determination of radiation dosimetry and initial clinical safety profile of radiotracer [11C]rolipram.
Goal 2: Demonstration of the in vivo distribution of (-)- and (+)-[11C]rolipram in the living human brain.
Goal 3: Demonstration of in vivo blockade with a competitor for [11C]rolipram.
For Goal 1 (determination of the radiation dosimetry and safety of the tracer), we will perform one whole body scan on four healthy subjects (1 scan/subject). Two subjects will receive injections of (-)-[11C]rolipram and two will receive an injection of (+)-[11C]rolipram. A whole-body dynamic scan will be performed over 100 minutes using a combined PET/CT (computed tomography) scanner.
For Goal 2 (demonstration and determination of the exact specificity and non-specific binding of the tracer), we will perform dynamic PET scans using both the -(-) and -(+) isomers of [11C]rolipram. Two scans each (one for each isomer) will be performed on two subjects. To quantify PDE4 activity, we will compare the binding of the inactive isomer to the active isomer of rolipram to estimate specific binding.
For Goal 3, once the radiation dosimetry, clinical safety, and specific binding have been determined, we will perform blocking studies. Subjects will be recruited to receive two 90-minute PET scans with -(-)[11C]rolipram: one before and one after a pretreatment with a competitor for [11C]rolipram. The same set of scans will also be performed with (-)+[11C]rolipram. We will test out several putative blockers of rolipram binding. It is expected that competitive inhibitors will block the active -(-) isomer but not the inactive –(+) isomer.