Synthesis and biological evaluation of novel 123I-labeled 4-(4-iodophenyl)butanoyl-l-prolyl-(2S)-pyrrolidines for imaging prolyl oligopeptidase in vivo

• 123I-labeled prolylpyrrolidines were synthesized for imaging prolyl oligopeptidase.
• The binding affinities of 123I-radiotracers were at low nanomolar range.
• 4-(4-[123I]iodophenyl)butanoyl-l-prolyl-2(S)-cyanopyrrolidine was evaluated in vivo.
• The binding of evaluated tracer was prolyl oligopeptidase specific.
• The tracer was further evaluated in two animal models of inflammation.

Prolyl oligopeptidase (POP) may be associated with neuromodulation and development of neurodegenerative diseases and it was recently shown to participate in the inflammatory cascade along with matrix metalloproteinases. Radiotracers, which can be used for non-invasive imaging, are needed for investigating the role of POP in normal physiology and in pathophysiological conditions in vivo. We synthesized two novel POP-specific 123I-radiolabeled 4-phenylbutanoyl-l-prolyl-pyrrolidines of which 4-(4-[123I]iodophenyl)butanoyl-l-prolyl-2(S)-cyanopyrrolidine ([123I]2f, Ki = 4.2 nM) was selected. The selected compound has an electrophilic cyano group that is known to increase the dissociation time of POP inhibitors. [123I]2f was synthesized in high radiochemical yield and purity (87 ± 4%, >99%, respectively) and with a specific activity of 456 ± 98 GBq/μmol. [123I]2f was evaluated in healthy mice (C57Bl/6JRccHsd) by ex vivo biodistribution studies and SPECT imaging. Pretreatment with the known inhibitor 4-phenylbutanoyl-l-prolyl-(2S)-cyanopyrrolidine (KYP-2047, 2d, Ki = 0.023 nM) showed that binding of [123I]2f was POP specific. In addition, [123I]2f was evaluated in models of neuroinflammation and acute localized inflammation. A minor increase in binding of [123I]2f was observed in the inflamed region in the acute localized inflammation model. Similar increase in binding was not observed in the neuroinflammation model.

Two new prolyl oligopeptidase (POP) inhibitors [123I]2e and [123I]2f were synthesized and evaluated as potential radiotracers for imaging POP with single photon emission tomography (SPECT).Figure optionsDownload as PowerPoint slide