Development of Aberrant Cdk5 imaging agent for early detection ofAlzheimer's disease pathology and treatment outcome measurement

Effective treatment for 5.5 million Americans with Alzheimer’s disease (AD) is desperately needed, as this irreversible brain disorder is the third leading cause of death in people aged 65 or older, and the leading cause of dementia. However, previous failed AD drug trials indicated that disease-modifying drugs need to be targeted to early-stages of AD to enable halting of the disease before significant damage has occurred. For this early-stage disease targeting therapeutic intervention, robust methods to detect early abnormal changes in the brain must be developed, highlighting an urgent need for a diagnostic biomarker for the early detection of AD pathology. Current AD biomarkers are mainly used at late-stage or for differential diagnosis of AD patients. Measurements of these biomarkers do not satisfy unmet clinical needs, as they do not offer effective diagnosis at the pre-symptomatic stage of disease progression (pre-symptomatic AD to Mild Cognitive Impairment (MCI) stage of AD). One potential biomarker that might facilitate early detection of early-stage pathology and disease progression in high-risk populations who could potentially develop AD is aberrant cyclin-dependent kinase 5 (aCdk5), which is generated during neurotoxic stress conditions. Previous studies demonstrated that induction of aCdk5 activity occurs prior to AD pathology. Aestasandapos;s diagnostic neuroimaging candidate targets disease- specific aCdk5, without interfering with normal functions. aCdk5 is considered a andquot;unifying upstreamandquot; event in the development of AD pathologies. Aestas Pharma will develop an aCdk5 PET Imaging Agent, AP-251-X, as a first- in-class non-invasive biomarker detection agent for the early detection of AD pathology. This diagnostic approach has the potential to facilitate detecting AD pathology earlier than existing biomarkers and may also be used alongside aCdk5-based therapeutics or other drug candidates as a diagnostic imaging agent to measure the target engagement or efficacy of the therapeutics and monitor outcomes. AP-251-X links a radiotracer for neuroimaging to a small, highly specific aCdk5 inhibitory peptide (AP-PEP31) exclusively licensed from NIH. Aim 1 is to develop radioligands that are suitable as diagnostic imaging agents. We will apply these compounds to PET neuroimaging in both male and female AD model mouse brains for early detection of pathology. Aim 2 is to test the feasibility of a lead radioligand as a tool to measure the AD treatment outcome in the AD model. We will treat symptomatic and asymptomatic AD mice with an aCdk5 blocker drug and our radioligand as a tool to determine the reversal of AD-like pathologies. Successful completion of SBIR Phase I studies will result in Aestas Pharma developing an aCdk5-selective diagnostic for early detection of Alzheimer’s disease in a mouse model. In the next several years, we plan to commercialize the agent for screening high-risk populations and for monitoring AD treatments with aCdk5-based therapeutics or other AD drugs.A new method to detect pathologic changes in the brain for early detection of Alzheimer’s Disease pathology is desperately needed for early diagnosis. Aberrant cyclin-dependent kinase 5 (aCdk5) is a unifying upstream event in the development of AD pathology. Aestas Pharma will develop radioligands to detect aCdk5 that are suitable as diagnostic imaging agents and treatment outcome measurements.