PET Imaging Agents for the in vivo Detection of TDP-43

Amyotrophic lateral sclerosisALSand frontotemperal lobar degenerationFTLDare debilitating neurological disorders that cause extreme suffering to patients and caregivers alikeAffected neurons in the spinal cord and brain of patients with ALS and FTLD are characterized for many individuals by having too much ubiquinylated and misfolded inclusions of cytosolic trans activating responseTARDNA binding protein TDPIt is estimated that half of FTLD patients have associated TDPpathologymaking TDPassociated FTLD the single largest subtypeTDPis also a key component of the ubiquitinated inclusions found in the cytosol of most patients with ALSespecially sporadic ALSsALSof patientsIn additionnumerous mutations in TDPparticularly in the glycine rich C terminal domainare linked to familial ALSfALSThe translational research effort described in this grant application seeks to identify selective radiotracers that image TDPin real time in the brain or spinal cord of relevant patient via positron emission tomographyPETUnlike for amyloide gflorbetapirand tauno TDPradiotracers have been reported to datePET ligands for ALS and FTLD are expected to provide early and more accurate diagnosis of diseasehelp to monitor the progression of disease over timeand evaluate whether various therapeutic treatments are having a positive effect in individual patientsWe have discovered new small molecule probes that bind to TDPusing an alpha screen assay that we developedand here propose to further refine and validate these as radiotracersincluding in animal models such as transgenic mice and normal non human primatesAimis to obtain more potent TDPbinders as candidates forF orC hot ligand synthesisby conducting iterative SAR development preparingnew chemical entitiesNCEsto obtain small molecule candidates that bind to TDPwith PET suitable biophysical propertiesusing modern methods of medicinal chemistrystructure based designpharmacophore development and synthetic chemistryBiochemical characterization will use our alpha screen assay and evaluation of binding to pathologically relevant misfolded TDPADME characterization will ensure that the biophysical properties of the top leads selected are amenable for PETIn Aimwe will prepare radiolabeled TDPbinding ligands suitable for in vivo imaging based on top Aimleadsan area of expertise for which Marty PomperJohns Hopkinskey personnel on the applicationhas considerable experienceFinallyin Aimwe seek to validate one or more TDPPET ligands using ex vivo and in vivo methods including in vivo characterization in TDPtransgenic miceTDPNLS mice and normal non human primateswith a desired outcome of rtspecific TDPblockadeIt is expected that at the end of this two year funding period we will have in hand at least one compound en route to an IND applicationAn example of commercial use would be to confirm a TDPbased diagnosis for dementia caused by FTLDwhen compared to the amyloid associated Alzheimer s disease