Imaging Second Messenger Systems Using [11C] Rolipram

Dean F. Wong, M.D., Ph.D.

Johns Hopkins University School of Medicine

Funded in June, 2005: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS .

LAY SUMMARY

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Testing a New PET Imaging Agent for Use in Evaluating Psychiatric Drug Therapies

Researchers will test in healthy human volunteers the safety and utility of a new PET imaging agent intended to be used to assess the effectiveness of various drugs used to treat psychiatric illnesses, such as schizophrenia, anxiety, depression, and addiction.

Psychiatric disorders are thought to involve malfunctions not only in certain neurotransmitters, such as serotonin, but also in “second messengers.” These are enzymes that continue to process the chemical messages transmitted from one brain cell to another.  PDE4 is second-messenger enzyme that is implicated in depression and other psychiatric disorders.  The researchers have converted a drug used to treat depression, called rolipram, into a PET radiotracer.  Rolipram binds to the PDE4 enzyme, permitting PET imaging to visualize the enzyme’s actions.  Now, the investigators will determine the radiotracer’s safety profile and its feasibility as a PET imaging tool.  The investigators will develop mathematical models from their PET studies to quantify normal and abnormal levels of this second-messenger enzyme.  Based on the findings, the researchers will apply to other funders for larger-scale support to use this new PET radiotracer to study the course of depression and other psychiatric disorders and to monitor the effects of various drug treatments on levels of the second-messenger enzyme.

Significance:  This new PET radiotracer could become an important tool in understanding the chemical actions involved in psychiatric disorders such as depression, schizophrenia, and anxiety.  It could provide a means to monitor the course of these diseases, and to assess the effectiveness of various experimental drugs, which act on the brain chemicals involved in these disorders.   

ABSTRACT

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Imaging Second Messenger Systems Using [11C] Rolipram

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 PDE IV activity. In this study, we will be conducting preliminary radiation dosimetry and specific binding studies to characterize this new radiotracer. We will then continue to blocking and challenge studies so that we can characterize PDE IV activity.

HYPOTHESIS

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Hypothesis:
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.

Goals:
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.

Methods:
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.