PET Imaging of Brain mGluR5 Receptors Using [18F]SP203
Condition: Healthy; Glutamate Receptor; mGlur5 Protein; Excitatory Amino Acid Receptors; Drug Kinetics; PET Scan
Study type: Interventional
Phase: Phase 1

Summary: 
      The metabotropic glutamate subtype five (mGluR5) receptor is a protein found in the brain and
      is the target for the excitatory chemical messenger glutimate. The purpose of this protocol
      is to measure mGluR5 receptors in the brain using positron emission tomography (PET) and a
      research drug called [18F]SP203.
    

Detailed description: 
      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.
    

Intervention name(s): [18F]SP203
Intervention type(s): Drug
Primary purpose: Treatment
Keywords: Pharmacokinetics; Binding Potential; Glutamate; Positron Emission Tomography; Metabolic Glutamate Receptors; Healthy Volunteer; HV