San Antonio Ligand Consortium (SALC)
The San Antonio Ligand Consortium (SALC) seeks to develop selective alpha-Synuclein (a-Syn) and 4R tau PET radiotracers for use in Parkinson???s disease (PD). non-Alzheimer???s disease (non-AD) tauopathies and related disorders. This goal is pursued via a tapering pipeline for: tracer design (Aim 1); tracer synthesis. characterization and prioritization (Aim 2); and validation (Aim 3).The overall project is developed to design highly specific 4R tau and a-Syn ligands from design through clinical translation. Our approach begins with a pre-selected common chemical Core that was identified during our preliminary investigations. There are specific features of the Core structure that qualifies for this purpose. Four Cores were designed based on our review of the CNS PET-tracer literature and by applying our own structural insights for developing brain penetrating PET ligands. Two of the proposed Cores were already tested in tau tracer development for AD imaging. We propose Cores that possess diverse biological properties related to synucleinopathies. Carboline and carbazole derivatives exhibit promising pharmacological activities in AD. epilepsy and other disorders. Initial high throughput in silico screening will be performed to select two subsets of compounds that are highly specific for each target protein. These compounds will serve as seed structures for focused library generation. In silico screening of these compound libraries will provide the specific binding capacities towards the individual target that will be evaluated in vitro. This campaign will undergo the SAR/medicinal chemistry optimization to select the candidates for a-Syn and 4R tau targeted in vivo imaging studies.Dr. McHardy???s lab at UTSA and the CIDD will execute the synthesis routes and prepare the targeted analogs. preparing 10-20 mg of each analog with a targeted purity of >96%. as assessed by 1H NMR and HPLC/MS.Each analog prepared will be registered in the CIDD cheminformatics database and assigned a CIDD compound number.A 5-10 mg sample of the analog will be shipped to Dr. Ramesh Neelamegam???s lab at UT Health SA (along with a delivery sheet and compound supporting information) and the remaining supply of the compound will be retained as a storage sample in a designated storage area/fridge in the CIDD.It is estimated that the CIDD will target the preparation of 30-40 novel analogs in year 1 of the grant to establish SAR and meet the goals of the program.