The goal of this research project is to determine if it is possible to develop a PET radiotracer capable of imaging GPCR heterodimers and not their corresponding homodimeric complexes. GPCR heterodimers represent the functional state of these receptors, yet there is currently no method for imaging these receptors in vivo with PET. Our initial strategy will focus on the development of probes for imaging the dopamine D2- adenosine A2A (i.e, D2/A2A) heterodimer. This heterodimer was chosen since it is currently thought to represent the main D2-coupled heterodimer in the CNS, and alterations in the D2/A2A heterodimer have been linked to a number of CNS disorders. Our strategy involves a novel approach that is focused on developing probes having an adequate affinity for binding to the D2/A2A heterodimer in vivo, but the affinity for the corresponding D2- and A2A homodimers is below the threshold needed to produce a signal in PET imaging studies. If successful, this proof-of-concept study will provide a new method for neuroreceptor imaging, PET imaging studies of GPCR heterodimers. Furthermore, the method we will develop can be applied to other orthosteric ligands to produce bivalent PET radiotracers capable of imaging different GPCR heterodimers, thereby ushering in a new era of PET radiotracer development for imaging this biologically important class of receptors.
The goal of the research described in this grant proposal is to conduct a proof-of-concept study aimed at developing PET radiotracers capable of binding GPCR heterodimers versus their corresponding homodimeric complexes. The projects focuses on the development of probes for imaging the D2/A2A heterodimer as a test case for determining the feasibility of this approach. If successful, this project will introduce a new avenue of research for neuroreceptor imaging with PET.
