PET Imaging of Brain mGluR5 Receptors Using [18F]SP203

Metabotropic glutamate receptors are G-protein coupled receptors that respond to glutamate by
activating proteins inside nerve cells that affect cell metabolism, thereby fine-tuning the
signals sent between cells to maintain balance in neuronal activity. Metabotropic Glutamate
receptors (mGluR5) are Group I receptors localized post-synaptically and found in several
regions of the brain including the striatum, hippocampus, amygdala, and cortex. Activation of
mGluR5 stimulates phospholipase C, resulting in phosphoinositide hydrolysis and increase of
intracellular Ca2+ levels. Several potent antagonists for mGluR5 have been developed,
including 6 methyl-2-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4yl)ethynyl]
pyridine (MTEP) however, no simple derivatives of MPEP or MTEP had proven to be useful for in
vivo imaging.

In the present protocol, we will use a new PET ligand [(18)F]SP203 for two reasons: Part 1.)
we will perform kinetic brain imaging to quantify mGluR5 binding parameters in brain and
determine the reliability and reproducibility of these measures in 15 healthy controls Part
2.) if the tracer is proved successful in the part 1, we plan to estimate radiation-absorbed
doses of [(18)F]SP203 in healthy human subjects by performing whole body imaging.

We will also use another new ligand, [11C]SP203, which has the same structure as [(18)F]SP203
but labeled with (11)C instead of (18)F. Part 3) the same purpose as part 1 but with
[(11)C]SP203 instead of [(18)F]SP203. Part 4) if [(11)C]SP203 is proved successful in the
part 3, we plan to estimate radiation absorbed doses of [(11)C]SP203 in healthy human
subjects. At this moment, we do not plan to perform additional scans of [(18)F]SP203 under
the current protocol. All future subjects will participate in scans of [(11)C]SP203.

Additionally, Part 5) we will measure the difference in [(18)F]SP203 concentration between
the artery and the vein without PET scanning to assess whether the venous blood is a valid
and less invasive substitute of arterial blood. In some of [(18)F]SP203 scans performed in
the current protocol, we compared [(18)F]SP203 levels between radial artery and antecubital
vein and observed 30% - 60% lower levels in vein. We plan to test whether sampling from a
vein in the hand and / or warming up makes [(18)F]SP203 levels in vein similar to artery.

Successful development of a PET ligand to image mGluR5 will have a strong impact on clinical
management of brain disorders with disruptions in glutamatergic transmission such as
schizophrenia, anxiety, and neurodegenerative disorders including Alzheimer s and Parkinson s
disease.

- INCLUSION CRITERIA:

Healthy control subjects aged 18 65 years, with history/physical exam, ECG, and laboratory
tests within one year of the PET scan within normal limits.

EXCLUSION CRITERIA:

1. Current psychiatric illness, substance abuse or severe systemic disease based on
history and physical exam.

2. Laboratory tests with clinically significant abnormalities.

3. Prior participation in other research protocols or clinical care in the last year such
that radiation exposure would exceed the annual limits.

4. Pregnancy and breast feeding.

5. Claustrophobia. (part 1 and 3 only)

6. Presence of ferromagnetic metal in the body or heart pacemaker. (part 1 and 3 only)

7. Positive HIV test.

8. Consumed alcohol within 48 hours before the PET scan.