Radiosynthesis of carbon-11-labelled GI181771, a new selective CCK-A agonist

The novel CCK-A agonist, (S)-3-(3-{1-[(isopropylphenylcarbamoyl)methyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}ureido)benzoic acid, GI181771 ((S)-1) has been isotopically labelled with carbon-11 at its urea site using [11C]phosgene in a one-pot two-step process, via the intermediate preparation of an [11C]isocyanate derivative. Optimized conditions for the preparation of (S)-[11C]-1 were the following: (1) Trapping of [11C]phosgene (radiosynthesized from cyclotron-produced [11C]methane via [11C]carbon tetrachloride using minor modifications of published processes) at room temperature for 1–2 min in 300 µl of acetonitrile containing 0.6 µmol of the appropriate (structurally complex) chiral-amine giving the corresponding [11C]isocyanate followed by (2) addition of an excess of 3-aminobenzoic acid (40 µmol in 100 µl of THF) as the second amine giving the desired urea derivative (S)-[11C]-1 and (3) high-performance liquid chromatography (HPLC) purification on a semi-preparative Waters Symmetry® C18. Starting from a typical 1.2 Ci (44.4 GBq) batch of [11C]methane, 25–35 mCi (0.92–1.29 GBq, 6.8–9.6% decay-corrected yield based on starting [11C] methane, n = 5) of (S)-[11C]-1 could be obtained within 35 min of radiosynthesis (HPLC purification and formulation as an i.v. injectable solution using a home-made Sep-pak®Plus C18 device included) with specific radioactivities ranging from 500 to 1500 mCi/µmol (18.5–55.5 GBq/µmol). The radiotracer preparation was a clear and colourless solution and its pH was between 5 and 7. As demonstrated by HPLC analysis, the radiolabelled product was found to be >99% chemically and radiochemically pure and the preparation was shown to be free of non-radioactive precursors (starting amines) and radiochemically stable for at least 60 min. Finally, enantiomeric purity was found to be >99% according to chiral HPLC, demonstrating the absence of racemization during the process. Copyright © 2005 John Wiley & Sons, Ltd.