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Synthesis and radiosynthesis with a positron emitter of EP 00652218, a potent antagonist of NK1 receptor, and of a fluoro analog for in vivo evaluation of the substance P receptor by pet
Author(s) -
Guéret C.,
Le Bas M. D.,
Perrio C.,
Dauphin F,
Dhilly M.,
Chazalviel L.,
Emond P.,
Chalon S.,
Tymciu S.,
Guilloteau D.,
Lasne M.C.,
Barré L.
Publication year - 2001
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580440199
Subject(s) - nk1 receptor antagonist , chemistry , neurokinin a , radiosynthesis , substance p , receptor , neurokinin b , in vivo , tachykinin receptor 1 , antagonist , pharmacology , tachykinin receptor , stereochemistry , neuropeptide , biochemistry , medicine , microbiology and biotechnology , biology
Neurokinins (NKs) are the most important of the peptides released from neuronal sensory afferents. In mammals different NKs [substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)] act as neurotransmitters and neuromodulators.(1) The biological responses induced by these neuropeptides are mediated by three distinct receptors NK1, NK2 and NK3 respectively. The NK1 receptors are widely distributed throughout the CNS and peripheral nervous systems. In recent years, clinical studies with selective NK1 receptor antagonists showed results for the treatment of emesis, depression, anxiety, pain and migraine.(2) Since the discovery of the first selective non‐peptide NK1 antagonist CP‐96,345, a considerable research in this area has been developed by the pharmaceutical industry.(3) In 1995, Takeda company described a novel class of highly potent, selective, and orally active NK1 antagonists such as 6‐pyrido[3, 4‐b]pyridinecarboxamide derivatives.(4) In this series, EP 00652218 1 (Scheme 1) was shown to exhibit subnanomolar affinity (IC 50 : 0.21nM, in vitro inhibition of [ 125 I]‐BH‐SP binding in human IM‐9 cells) towards the NK1 receptors. Moreover, SAR studies demonstrated that the bis (trifluoromethylbenzyl) moiety was essential for the affinity. This led us to consider that EP 00652218 1 could be a good candidate for in vivo imaging of NK1 receptors and that the design of pyridine or phenyl ring substituted analogs would retain a high affinity. In order to develop ligands that could be used either in PET or SPECT studies, we undertook the synthesis of compounds bearing an halogen atom (fluorine, bromine or iodine). In this paper we report both the synthesis and labelling of the reference EP 00652218 1 with carbon‐11 and of the analog 2 with fluorine‐18 (Schemes 1, 2 and 3).