The epidermal growth factor receptor (EGFR) is an epithelial cell membrane receptor with an intra-cellular tyrosine kinase (TK) component. EGFR-TK is involved in cell signalling critical to proliferation, apoptosis, repair and angiogenesis. More than two thirds of human cancers derive from epithelial tissues and the EFGR-TK is overexpressed in the majority of these tumors. Thus in recent years numerous selective EGFR-TK inhibitors with nanomolar affinities have been developed as potential anti-cancer agents. One potent inhibitor that has progressed the furthest toward clinical registration is ZD1839 (or Iressa). ZD1839 is approved for clinical use in Japan and is close to obtaining U.S. FDA approva l. ZD1839 is a fluorine-containing anilinoquinazoline which can be isotopically labelled with 18 F for use in clinical oncology as a PET imaging agent. Since extensive pre-clinical and clinical data on ZD1839 are available, the use of 18 F-ZD1839 to identify patients who would benefit from Iressa treatment and monitor its efficacy would be straightforward.
While there have been studies on several EGFR-targeted PET imaging agents (1-6), results reported so far with these tracers have been disappointing. We recently began the development of a reliable and efficient synthetic route for the routine preparation of 18 F-ZD1839. Starting from 2nitro-4,5-dimethoxybenzoic acid methyl ester, a 9-step synthesis was performed to prepare 7methoxy-6-(3-morpholinopropoxy)-4-chloro-quinazoline (compound 10 below). This product was authenticated by proton NMR. Adapting methods reported by others (3-5), 18 F-ZD1839 was prepared starting with the standard Kryptofix-K2CO3-mediated nucleophilic 18 F exchange reaction with a trimethylammonium triflate precursor to give 4-[
18 F]fluoro-3-chloro-nitrobenzene (Scheme 1) with 50% non-decay corrected yield. Reduction with sodium borohydride gave 4-[ 18 F]fluoro-3chloro-aniline then condensation with compound 10 in DMF at 145 o C gave 18 F-ZD1839. The overall non-decay corrected 18 F-ZD1839 yield based on the starting 18 F-fluoride was 7% -10% after 150 min total reaction time including semi-preparative reverse phase HPLC purification. Initial biodistribution studies in normal HSD-ICR mice showed high uptake of 18 F-ZD1839 in the GI tract, liver, kidneys and bladder consistent with the known high EGFR localization in these organs. Plasma metabolite analysis in several mice up to 3 hr showed temporally decreasing percentage of unchanged 18 F-ZD1839 declining to 52% at 3 hr postinjection. Dynamic PET studies of mice using a Concorde microPET P4 scanner are underway.