Quantification methods for brain imaging with novel and repurposed PET tracers

The number of people suffering from brain disorders is annually increasing. Knowledge about the molecular processes in the healthy and diseased brain is essential for a better understanding of disease conditions, treatment selection, and drug development. Positron emission tomography (PET) is a noninvasive imaging technique that can be used to acquire information about processes that are essential for normal brain functioning, but are altered in neurodegenerative diseases. Quantitative information about specific targets inside the brain, such as the density, activity, or occupancy of particular enzymes, transporters, or receptors, can be obtained by pharmacokinetic modeling of PET data. In the present study, we assessed quantification methods for brain imaging with novel and repurposed PET tracers. A PET tracer for inflammation in the brain, called [11C]SC-560, was evaluated, but overexpression of the inflammatory marker COX-1, could not be detected in the inflamed rat brain. Thus, more efforts to find an appropriate tracer are required. Next, we determined the optimal method for quantification of histamine H3 receptors in the rat brain, using PET and the radiotracer [11C]GSK-189254. Blockade of these receptors may improve cognition in patients with dementia. [11C]GSK-189254 PET and [11C]raclopride PET were subsequently used to measure the dose-dependent occupancy of histamine H3 and dopamine D2 receptors in the brain of living rats by the investigational drug AG-0029. D2 receptors play an important role in motor control. Since AG-0029 blocks histamine H3 receptors and stimulates dopamine D2 receptors, AG-0029 is a candidate drug for treatment of Parkinson disease. Finally, we evaluated the feasibility of quantifying the expression of estrogen receptors in the brains of post-menopausal women with [18F]FES PET. We were able to detect estrogen receptors in brain regions with a high density of the receptor (i.e., the pituitary). The methods described in this study may be used to enhance knowledge about the brain, the treatment of brain diseases and the development of novel drugs.