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Synthesis and evaluation of 5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[ 18 F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid as a potential NMDA ligand to study glutamatergic neurotransmission in vivo
Author(s) -
Piel Markus,
Schirrmacher Ralf,
Höhnemann Sabine,
Hamkens Wilhelm,
Kohl Beate,
Jansen Michaela,
Schmitt Ullrich,
Lüddens Hartmut,
Dannhardt Gerd,
Rösch Frank
Publication year - 2003
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.682
Subject(s) - chemistry , biodistribution , radiosynthesis , ligand (biochemistry) , lipophilicity , carboxylic acid , moiety , stereochemistry , ex vivo , radioligand , in vivo , receptor , organic chemistry , in vitro , biochemistry , microbiology and biotechnology , biology
The neurotransmitter glutamate is thought to be crucially involved in a huge number of neurological and psychiatric disorders, such as Morbus Parkinson, Alzheimer's disease and schizophrenia. Aiming at an improved diagnostic tool for PET a new [ 18 F]fluorine labelled NMDA receptor ligand was developed that may potentially allow the in vivo visualization of glutama‐tergic neurotransmission. The 19 F‐analogue trans ‐5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydro quinoline‐2‐carboxylic acid was synthesised to determine the binding affinity, lipophilicity and biodistribution of the ligand. This substance exhibits a K i of 12 nM for the glycine binding site using [ 3 H]MDL‐105,519 assays on pig cortical membranes. A logD of 1.3 was determined for this compound according to the OECD guidelines employing the HPLC method. Radiosynthesis of this ligand was achieved by labelling the precursor trans ‐5,7‐dichloro‐4‐[3‐(4‐piperazin‐1‐yl‐phenyl)‐ureido]‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid methyl ester with 2‐[ 18 F]fluoroethyltosylate and subsequent cleaving of the methyl ester moiety, resulting in an overall decay corrected yield of 35% of the final product trans ‐5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[ 18 F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid. The biodistribution kinetics of this compound were determined with Sprague Dawley rats ex vivo for brain, liver, kidney, and bone. The ligand showed a maximum brain uptake 30 min.p.i. of about 0.1% ID/g. Copyright © 2003 John Wiley & Sons, Ltd.