Synthesis and biological evaluation of novel (123)I-labeled 4-(4-iodophenyl)butanoyl-L-prolyl-(2S)-pyrrolidines for imaging prolyl oligopeptidase in vivo.
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 (123)I-radiolabeled 4-phenylbutanoyl-L-prolyl-pyrrolidines of which 4-(4-[(123)I]iodophenyl)butanoyl-L-prolyl-2(S)-cyanopyrrolidine ([(123)I]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. [(123)I]2f was synthesized in high radiochemical yield and purity (87 ± 4%, >99%, respectively) and with a specific activity of 456 ± 98 GBq/μmol. [(123)I]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 [(123)I]2f was POP specific. In addition, [(123)I]2f was evaluated in models of neuroinflammation and acute localized inflammation. A minor increase in binding of [(123)I]2f was observed in the inflamed region in the acute localized inflammation model. Similar increase in binding was not observed in the neuroinflammation model.
Laboratory of Radiochemistry, Department of Chemistry, P.O. Box 55, FI-00014 University of Helsinki, Finland. Electronic address: annukka.kallinen@helsinki.fi.
Annukka
A
Kallinen
Laboratory of Radiochemistry, Department of Chemistry, P.O. Box 55, FI-00014 University of Helsinki, Finland.
Boyan
B
Todorov
Division of Pharmaceutical Chemistry, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
Roope
R
Kallionpää
Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
Susanne
S
Bäck
Laboratory of Radiochemistry, Department of Chemistry, P.O. Box 55, FI-00014 University of Helsinki, Finland.
Mirkka
M
Sarparanta
Centre for Drug Research, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
Mari
M
Raki
Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
Juan A
JA
García-Horsman
Centre for Drug Research, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland; HUS Medical Imaging Center, Helsinki University Central Hospital, Finland.
Kim A
KA
Bergström
Division of Pharmaceutical Chemistry, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
Erik A A
EA
Wallén
Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
Pekka T
PT
Männistö
Laboratory of Radiochemistry, Department of Chemistry, P.O. Box 55, FI-00014 University of Helsinki, Finland. Electronic address: anu.airaksinen@helsinki.fi.
Anu J
AJ
Airaksinen
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
C000594271:4-(4-((123)I)iodophenyl)butanoyl-L-prolyl-2(S)-cyanopyrrolidine; D007457:Iodine Radioisotopes; D009570:Nitriles; D011759:Pyrrolidines; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases
(123)I-radiotracer; Biodistribution; Inflammation; Prolyl oligopeptidase