The receptor for advanced glycation endproducts (RAGE) is a membrane-bound receptor implicated in diseases of inflammation. Increased levels of RAGE have also been identified in post-mortem brain sections of patients with neurodegenerative disorders. With the goal of understanding RAGE’s, and inflammation’s, role in neurodegenerative disease, we aimed to develop PET tracers for the extra- and intracellular membranes of RAGE. There a multiple isoforms of RAGE, including a circulating soluble form with a possible role as a scavenger receptor and its distinct role in disease progression is unknown. We developed the first small molecule radioligand for the extracellular domain, [18F]RAGER. It has high affinity for RAGE (Kd = 15 nM), shows specific binding in Alzheimer's disease brain sections and colocalizes with RAGE immunohistochemistry, has good CNS penetration in rat and monkey, and increased uptake in areas of the brain known to express RAGE. Biodistribution studies were performed in Sprague Dawley rat and confirmed rapid brain uptake. Screening for possible CNS off target binding returned &gt;90% inhibition at 10 µM (melatonin MT1; Ki = 93 nM); however, blocking studies in nonhuman primate demonstrated in vivo no significant binding to MT1. In addition to this extracellular radioligand, we developed [18F]InRAGER, which binds to the intracellular face of RAGE and is only present in the full length form. [18F]InRAGER (Kd= 1nM) was synthesized in relatively low yield from halogen exchange, radiochemical yield being 1%. Small animal PET imaging revealed that it is blood-brain barrier permeable in rodents. Further evaluation of this radioligand including an optimized radiosynthesis to increase specific molar activity and radiochemical yield, specific binding evaluation on post-mortem human brain tissue, and small animal PET imaging in nonhuman primate will be reported. The combined use of extra and intracellular radioligands will assist in the ongoing investigation into the roles of soluble RAGE and the full length receptor in neuroinflammation.

Two strategies for imaging the receptor for advanced glycation end products

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.