Pyrrolo[2,3-c]pyridines as Imaging Agents for Neurofibrilary Tangles.

Abstract

Tau protein and tau aggregates Summary: Alzheimer’s disease (AD), a neurodegenerative disorder characterized by neuronal and synaptic loss, brain atrophy, and slow, progressive dementia first characterized by Dr. Alois Alzheimer in 1901, remains a major unmet medical need. Despite decades of research, a cure remains elusive and treatment options are limited. In 2015, approximately 5.3 million US citizens had Alzheimer’s disease, and the direct cost of AD patient care in the US was ∼$226 billion. In the absence of novel therapies, the US AD patient population is expected to exceed 13.8 million by 2050, and the cost of care will balloon to over $1.1 trillion. Although the pathogenesis of AD has not been determined, there are two major theories that describe its pathogenesis, the amyloid hypothesisandthetautheory.Accordingtotheamyloidhypothesistheneurodegenerationandlossofcognitivefunctionassociated withADare causedbythe buildupof β-amyloidplaques.These plaquesarebelievedtobe theresultofimproperamyloidprecursor protein(APP)processingby β-secretase(BACE)and γ-secretase,whichleadstoabuildupoftheAβ-42 fragmentofAPP.Aβ-42is prone to aggregation and plaque formation, and it has been hypothesized that preventing the formation and/or clearing these materials from the brain will arrest AD progression. Thetautheory,however,hypothesizesthatADpathogenesisiscausedbymishandlingoftubulin-associatedunit(tau)proteins.Under normalconditions,thishighlysolublemicrotubuleassociatedproteinmodulatesthestabilityofaxonalmicrotubules.InADpatients, however, tau becomes hyperphosphorylated, which substantially decreases its solubility. This leads to the formation of tau aggregates and neurofibrillary tangles inside nerve cells. This, in turn, causes neuron death, cognitive impairment, and other symptoms of AD. Diagnostictoolscapableofdetectingthepresenceofeither β-amyloidplaquesortauaggregatescouldprovideamethodofdiagnosing AD. The present disclosure describes a series of pyrrolo[2,3-c]pyridines useful as positron emission tomography (PET) imaging agents capable of binding to tau aggregates.