New F-18 Prosthetic Group via Oxime Coupling

Abstract

A novel fluorine-18 prosthetic ligand, 5-(1,3-dioxolan-2-yl)-2-(2-(2-(2- fluoroethoxy)ethoxy)ethoxy)pyridine [18F]2, has been synthesized. The prosthetic ligand is formed in high radiochemical yield (rcy = 71 ± 2 %, n = 3) with excellent radiochemical purity (rcp = 99 ± 1 %, n = 3) in a short reaction time (10 min). [18F]2 is a small, neutral, organic complex, easily synthesized in four steps from a readily available starting material. It can be anchored onto a target molecule containing an aminooxy functional group under acidic conditions by way of an oxime bond. We report herein two examples [18F]23 and [18F]24, potential imaging agents for β-amyloid plaques, which were labeled with this prosthetic group. This approach could be used for labeling proteins and peptides containing an aminooxy group. Biodistribution in male ICR mice for both oxime labeled complexes [18F]23 and [18F]24 were compared to that of the known β-amyloid plaque indicator, [18F]-AV-45, florbetapir 1. Oximes [18F]23 and [18F]24 are larger in size and therefore should reduce the blood-brain barrier (BBB) penetration. The brain uptake for oxime [18F]23 appeared to be reduced, but still retained some capability to cross the BBB. Oxime [18F]24 showed promising results after 2 min post injection (0.48 % dose/gram), however the uptake increased after 30 min post injection (0.92 % dose/gram) suggesting an in-vivo decomposition/metabolism of compound [18F]24. We have demonstrated a general protocol for the fluoride-18 labeling with a new prosthetic ligand [18F]2 that is tolerant towards several functional groups and is formed via chemoselective oxime coupling.

Fluorine-18 labelled building blocks for PET tracer synthesis

“…Two model compounds 335a and b, both potential tracers for b-amyloid plaque imaging, were synthesised by Carberry et al using building block 334 and were obtained in comparable overall radiochemical yields (around 40% (dc)) in 100 minutes (Scheme 60). 235 Successful labelling of small molecules using this building block has been demonstrated. The utility of this prosthetic group in radiofluorination of more complex biomolecules such as peptides and proteins has yet to be proven.…”

Borylated oximes: versatile building blocks for organic synthesis

“…16,30 Additionally, this methodology represents an attractive route to produce isotopically labelled peptides. 31 …”

Fluoride-18 radiolabeling of peptides bearing an aminooxy functional group to a prosthetic ligand via an oxime bond

“…22 Compound 1 was used to radiolabel two model aminooxy complexes, by way of oxime coupling, to provide the desired fluorine-18 radiotracers. The biodistribution in male ICR mice for both oxime labeled complexes were compared to that of the known β-amyloid plaque indicator, [ 18 F]-AV-45, florbetapir.…”

“…22 The synthesis begins with the protection of the aldehyde functionality of 6-bromo-3-pyridine carbaldehyde to afford acetal 2 28 (Scheme 1). A pegylated chain is then added onto the molecule and the alcohol function group is transformed into tosylate 5 .…”

“…It is extremely crucial in the radiolabeling step to have the aldehyde protected as the acetal to avoid side products. 22 The aldehyde functionality is then de-blocked in situ during the oxime coupling reaction rendering [ 18 F]-FPBA 1 .…”