Development of an alpha6*-Selective Neuronal Nicotinic Receptor (NNR) Imaging Agent as a Parkinson's Disease Biomarker
The availability of a selective PET radiotracer for the drug target is critical for determining receptor occupancy in humans. NNR subtypes containing the alpha? subunit have been shown to strongly influence motor behavior in preclinical models, and there is great interest in the nicotinic field in developing therapeutics with activity at alpha6-containing NNRs to treat the motor deficits of PD. However, there are no selective radiotracers for alpha6-containing NNRs that are suitable for PET imaging and receptor occupancy studies in humans. In addition, as the field moves toward developing therapeutics aimed at slowing the progression of Parkinson’s disease, it is becoming increasingly necessary to develop methods for early detection or confirmation of early stages of PD. Currently, the most common and sensitive imaging technique for early PD is assessment of dopamine transporter (DAT) levels. While changes in DAT have been detected in pre-motoric PD patients using PET radiotracers, we believe that physicians and their patients would benefit from improvements in sensitivity for measuring early-stage changes in PD pathology.
Targacept has developed one of the largest NNR-focused compound libraries in the pharmaceutical industry. This extensive compound library, along with the accompanying knowledge-base of the NNR target class, makes possible the identification of compounds that would also demonstrate qualities suitable for imaging alpha6beta2* NNR. Qualities that constitute an optimal PET ligand include high selectivity and affinity for alpha6beta2*, little if any non-specific binding, short & convergent syntheses, the ability to attach the imaging isotope readily late in the synthesis, high brain/plasma ratio and optimal brain kinetics. The identification of small molecules which interact with alpha6beta2* suitable for becoming an optimal PET radio-imaging tool may permit the early identification of aSymptoms & Side Effects individuals who would have a high likelihood of developing PD, as well as the assessment of receptor occupancy for drug therapies targeting the alpha6beta2* receptor in PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The goal of the proposed work is to identify, develop and demonstrate an early marker of Parkinson's disease (PD) that may hold the potential to identify disease onset prior to clinical manifestation. Recent evidence has demonstrated that alpha6beta2* NNRs are reduced in density PD subjects very early in disease progression. We seek to identify the first alpha6-specific NNR PET imaging agent which may serve as both a drug and disease biomarker for early detection of patients which would develop PD.
There currently exist no known alpha6-selective radioligands that are suitable for PET imaging agents. By targeting alpha6beta2* NNR subtypes with selective radiotracers, we may gain understanding of the pathophysiology of other striatal degenerations occurring during the development and progression of PD. An important question that could be addressed will be whether the selective loss of the very high affinity alpha6beta2* receptor is associated with any of the pre-motor symptoms of PD, such as depression, cognitive deficits, abnormal REM sleep, and loss of olfaction. This knowledge would be critical to the development of novel and improved drug therapies for PD.
The first part of this project focused on the synthesis of compounds and optimization on existing chemical scaffolds that were created by Targacept. Criteria for a good imaging agent were determined in consultation with collaborators at Molecular Neuroimaging, LLC. An initial radiolabel displacement assay was abandoned in favor of a rat brain autoradiography binding assay because the first assay was determined to be too variable. Additional screening is also being performed with follow-up SAR on hits. Leads have been identified that seem to be selective but will require further optimization. Some of the leads may be suitable for radiolabeling and ultimately for use as imaging agents.
Director, Drug Discovery at Targacept, Inc.
Location: Winston Salem, North Carolina, United States