Synthesis and evaluation of 5,7-dichloro-4-(3-{4-[4-(2-[18F]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

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 46; no. 7; pp. 645 - 659
• Main Authors: Piel, Markus, Schirrmacher, Ralf, Höhnemann, Sabine, Hamkens, Wilhelm, Kohl, Beate, Jansen, Michaela, Schmitt, Ullrich, Lüddens, Hartmut, Dannhardt, Gerd, Rösch, Frank
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.06.2003; Wiley
• Subjects: 18F-fluoroalkylation; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological and medical sciences; Chemistry; Chemistry, Analytical; Chemistry, Medicinal; Contrast media. Radiopharmaceuticals; Glutamate; Glycine binding site; Life Sciences & Biomedicine; Medical sciences; NMDA receptor; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Science & Technology; ANTAGONIST; GLYCINE SITE; RECEPTOR; F-18-fluoroalkylation; NMDA receptor; glycine binding site; glutamate; Intravenous administration; Fluorine 18; Rat; Nitrogen heterocycle; Ligand; Central nervous system; Glutamate receptor; Tissue; Ex vivo; Chlorine Organic compounds; Bicyclic compound; Ureas; Aromatic compound; Chemical synthesis; Ungulata; Haloalkylation; Fluorine Isotopes; Radiolabelling; Rodentia; In vitro; Pig; In vivo; Vertebrata; Biological fixation; Mammalia; Animal; Glycine receptor; Distribution; Affinity; Artiodactyla; Piperazine derivatives; Pharmacokinetics; Brain (vertebrata)
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.682

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 [18F]fluorine labelled NMDA receptor ligand was developed that may potentially allow the in vivo visualization of glutama‐tergic neurotransmission. The 19F‐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 Ki of 12 nM for the glycine binding site using [3H]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‐[18F]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‐[18F]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.