(300 WORDS MAX.)Risk presents a significant barrier against investigation of novel targets and drugs in neurodegenerative disease. In this domain, a huge component of risk comes from advancing lead molecules without understanding if they reach the human brain (the target organ) or engage their target. The costs of failure are astronomical. As a result, companies equipped to engage in phase II-III trials prioritize candidate molecules and associated data packages with a low relative risk of failure. Demonstrating brain uptake and quantitative target engagement is one of the best ways to de-risk a novel chemical tool for clinical trials.Among neurodegenerative diseases, histone deacetylase isoform 6 (HDAC6) represents a highly impactful treatment target especially in 'tauopathies' -- such as Alzheimer's disease (AD) and frontotemporal dementia. These diseases share the pathological feature of accumulated hyperphosphorylated tau and an inability to extricate neurofibrillary tangles (NFTs) from the brain. Dysfunctional acetylation of α-tubulin was first associated with NFTs and microtubule instability in AD more than 20 years ago. More recently, HDAC6 was described to have a central role in mediating acetylation of non-histone proteins including α-tubulin and tau, with mechanistic links to pathologies in neurodegenerative disease. Selective small molecule HDAC6 inhibitors exist, and have shown promise to prevent tau accumulation or to eradicate NFTs in animals. However, risk has stalled progress in translating these discoveries to the clinic. Our company, Eikonizo (Greek for 'envision' or 'imagine'), brings together expertise in epigenetics, small molecule design and in vivo neuroimaging. Through this proposal, our goal is to evaluate a novel, highly selective HDAC6 inhibitor with outstanding brain penetrance as a radiolabeled positron emission tomography imaging tool and therapeutic lead to target HDAC6 in humans. We have engineered our milestones to make go/no-go decisions at critical inflection points in order to efficiently establish or deprioritize HDAC6 as a therapeutic target.