Universität Zu Koln

Max-Planck-Gesellschaft Zur F&#xf6;rderung Der Wissenschaften E. V.

Raphael Richarz

Bernd Neumaier

Boris Zlatopolskiy

Philipp Krapf

Alexander Drzezga

Phillip Krapf

6-[F]Fluoro-2-alkoxynicotinoyl substituted Lys-C(O)-Glu derivatives were identified as efficient imaging probes for PSMA expressing tissues in comparison to other known PSMA specific ligands like [F]DCFPyL, [Ga]HBED-CC-PSMA, [F]PSMA-1007 and [AlF]HBED-CC-PSMA. Unexpectedly, the 6-[F]fluoro-2-alkoxy and 6-[F]fluoro-4-alkoxy substituted analogs showed significant differences in accumulation in PSMA expressing prostate tumor cells. Whereas the 2-alkoxy derivative showed cellular uptake values higher than [F]DCFPyL, the cellular uptake of the corresponding 4-alkoxy substituted derivative was significantly lower. Furthermore, in vivo PET studies with 2-alkoxy-substituted probes demonstrated excellent visualization of PSMA positive ganglia with extremely high target to background ratio. In contrast, the 4-alkoxy substituted derivatives showed less favorable biodistribution with significantly lower uptake in PSMA positive tissues. Especially, theF-labeled 2-methoxy derivate ((2S)-2-({[(1S)-1-carboxy-5-[(6-[F]fluoro-2-methoxypyridin-3-yl)formamido]pentyl]carbamoyl}-amino)pentanedioic acid) demonstrated exceptional clinical efficiency in detecting small PCa lesions, including those which could not be visualized with [Ga]HBED-CC-PSMA representing currently the gold standard for the diagnosis of recurrent PCa. Furthermore, this probe is easily accessible on a preparative scale in commercially available automated synthesis modules like GE FASTlab and TRACERlab FX N Pro. Consequently, the novel probe is a valuable tool for the visualization of ganglia and reendothelialization as well as for the diagnosis of glioma, neuropathic pain and atherosclerotic plaques.

2-alkoxy-6-[18F]fluoronicotinoyl substituted lys-c(O)-glu derivatives as efficient probes for imaging of PSMA expressing tissues

Novel efficient, time-saving and reliable radiofluorination procedures for the production ofF-labelled active esters via nucleophilic substitution of the corresponding onium precursors withFare described. The active ester including [F]F-Py-TFP and [F]TFB produced by one of these methods was used to prepare PSMA-specific PET tracers such as [F]DCFPyL. The key advantages of these inventive methods are efficiency, short time of preparation and excellent amenability to automation. A pharmaceutical composition containing at least one PSMA-specific PET tracers prepared by the inventive method is useful for positron emission tomography (PET) imaging, especially imaging prostate tumor.

Method for the production of 18F-labeled active esters and their application exemplified by the preparation of a PSMA-specific PET-tracer

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Leverkusen, Germany

Raphael Richarz