Heterocycle-Amide Isosteres: Application in the Development of Receptor-Based Imaging Agents for PET
Date of Award
Doctor of Philosophy (PhD)
Amide linkages are favored in medicinal chemistry to build molecule libraries because of their vast presence in biomolecules, such as peptides and proteins. In addition, molecules with amide linkages have more flexible conformation, thus these molecules are more likely to orient to a conformation that fits a protein's binding pocket.
Our group has been engaging in developing selective dopamine D3 receptor ligands and sigma-2 receptor ligands. In the past few years, amide linkages were employed in the majority of the dopamine D3 and sigma-2 ligands we have developed. Many of the benzamide ligands showed promising in vitro data, but few exhibit great in vivo characteristics. One of the reasons is that amide linkage was identified as a potential metabolic site for in vivo modification by proteases. My research explored new synthons as replacements for the amide linkages in dopamine D3 receptor ligands and sigma-2 receptor ligands. 5-Membered heterocycle rings, such as triazoles and isoxazoles, have been reported to exhibit resistance to metabolic degradation and represent novel isosteric substitution of an amide linkage. In addition, the hetero atoms may participate in hydrogen bonding and dipole-dipole interactions, which could result in more favorable receptor binding properties.
The second step of the research reported in this thesis is the development of selective dopamine D3 receptor tracers and sigma-2 receptor tracers for non-invasive Positron Emission Tomography (PET). Dopamine D3 receptors play an important role in Central Nervous System (CNS) and may be associated with several CNS diseases and behavioral disorders, including psychostimulant abuse. Sigma-2 receptors have been shown to be expressed in a variety of human tumors, in particular, those of breast, melanoma, non-small-cell lung carcinoma, brain, prostate and tumors of neural origin. Sigma-2 receptors are the only validated biomarker for imaging the proliferative status of tumor cells.
In this thesis, two dopamine D3 ligands were radiolabeled and evaluated in non-human primate microPET studies. Two sigma-2 ligands were also radiolabeled and evaluated in rodents bearing tumor cells. We have identified the two sigma-2 tracers [11C]PX-II-116]and [18F]PX-II-120]as promising PET tracers for imaging proliferative status of tumor cells.
Chair and Committee
Robert H Mach
Joshua Maurer, Joseph Ackerman, Peter Gaspar, Suzanne Lapi, John-Stephen Taylor
Peng, Xin, "Heterocycle-Amide Isosteres: Application in the Development of Receptor-Based Imaging Agents for PET" (2013). Arts & Sciences Electronic Theses and Dissertations. 162.