Radiolabeling of [ ¹¹ C]FPS-ZM1, a Receptor for Advanced Glycation End products-targeting Positron Emission Tomography radiotracer, Using a [ ¹¹ C]CO ₂ -to-[ ¹¹ C]CO Chemical Conversion

Abstract

Aim: The receptor for advanced glycation end products (RAGE) is a viable target for early Alzheimer’s disease (AD) diagnosis using positron emission tomography (PET) as RAGE overexpression precedes Aβ plaque formation. The development of a carbon-11 analog of FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide, [11C]FPS-ZM1), possessing nanomolar affinity for RAGE, may enable the imaging of RAGE for early AD detection. Methodology & results: Herein we report an optimized [11C]CO2-to-[11C]CO chemical conversion for the synthesis of [11C]FPS-ZM1 and in vitro brain autoradiography. The [11C]CO2-to-[11C]CO conversion via 11C-silanecarboxylate derivatives was achieved with a 57% yield within 30 s from end of [11C]CO2 delivery. [11C]FPS-ZM1 was obtained with a decay-corrected isolated radiochemical yield of 9.5%. Conclusion: [11C]FPS-ZM1 distribution in brain tissues of wild-type versus transgenic AD model mice showed no statistically significant difference and high nondisplaceable binding.

Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE)

“…RAGE is expressed ubiquitously at low levels in the CNS, but, unlike MT 1 , RAGE expression is inducible by the level of inflammation in the microenvironment, and increases in the presence of RAGE ligands such as cytokines or other proinflammatory mediators [ 27 ]. For example, RAGE is documented to be overexpressed in hippocampal neurons in AD [ 9 ], consistent with the increased binding of [ 18 F]RAGER and [ 11 C]FPS-ZM1 in autoradiography studies with rodent and human AD brain tissue samples described above and previously reported [ 17 , 21 ]. Studies with [ 18 F]RAGER show the highest uptake in the thalamus and basal ganglia in healthy nonhuman primates, which may overlap with areas of MT 1 expression [ 17 ].…”

“…[ 19 , 20 ] and Luzi et al. [ 21 ] have reported autoradiography and rodent imaging with [ 18 F]RAGER and [ 11 C]FPS-ZM1, respectively. The in vivo imaging studies are all in agreement that despite high (96%) plasma protein binding ( Fig.…”

“…[ 19 , 20 ] and Luzi et al. [ 21 ], respectively. In the present study, we build upon these initial reports and describe our further evaluation of RAGER and FPS-ZM1 as potential radiotracers targeting the extracellular domain of RAGE.…”

Progress of RAGE Molecular Imaging in Alzheimer’s Disease

“…These tau and Aβ-targeting probes can also be used for quantification analysis to further validate the role of RAGE in the pathogenesis of AD (Fang et al, 2018). As RAGE overexpression precedes Aβ plaque formation (Luzi et al, 2020), [ 18 F]-FPS-ZM1 PET/CT imaging is expected to be more sensitive than traditional Aβ imaging. It can monitor changes in cerebrovascular function over time and thus provide accurate, reliable, and reproducible non-invasive in vivo quantitative data for local or whole-brain pathological changes.…”

Welcome to Volume 13 of Future Medicinal Chemistry

“…Many research articles were published in Future Medicinal Chemistry last year that continue to be popular among our readers. Highlights include 'Pathway and mechanism of drug binding to chemokine receptors revealed by accelerated molecular simulations,' '3-amino-alkylated indoles: unexplored green products acting as anti-inflammatory agents' and 'Radiolabeling of [11C]FPS-ZM1, a receptor for advanced glycation end products-targeting positron emission tomography radiotracer, using a [11C]CO2-to-[11C]CO chemical conversion' [6][7][8].…”