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Combinatorial synthesis of labelled drugs and PET tracers: synthesis of a focused library of 11 C‐ carbonyl ‐labelled acrylamides as potential biomarkers of EGFR expression
Author(s) -
Åberg Ola,
Långström Bengt
Publication year - 2012
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.2981
Subject(s) - chemistry , carbon monoxide , electrophile , combinatorial chemistry , positron emission tomography , in vivo , nucleophile , bioorthogonal chemistry , epidermal growth factor receptor , radiochemistry , click chemistry , organic chemistry , receptor , nuclear medicine , biochemistry , medicine , microbiology and biotechnology , biology , catalysis
Combinatorial synthesis is extensively used in drug development and lead optimisation. However, this approach has rarely been used for positron emission tomography because of limitations in available technologies. [ 11 C]Carbon monoxide is amenable to combinatorial synthesis in transition‐metal‐catalysed reactions because it can react with a wide variety of electrophiles and nucleophiles, which opens up the possibilities for combinatorial radiochemistry. Herein, we exemplify the combinatorial approach by 11 C‐labelling a library of epidermal growth factor receptor inhibitors. The selection of candidates was guided by molecular docking. Epidermal growth factor receptor is overexpressed in a variety of tumours, and it has become an important drug target. The 11 C‐labelling reactions were performed using four substituted vinyl iodides and three different 4‐anilino‐6‐aminoquinazolines using a palladium‐mediated reaction with [ 11 C]carbon monoxide using a single set of reaction conditions. In total, 12 labelled acrylamide derivatives were radiolabelled and obtained in 24–61% decay‐corrected radiochemical yield (from [ 11 C]carbon monoxide). Starting from 5.6 GBq [ 11 C]carbon monoxide, 0.85 GBq of formulated N ‐[4‐(3‐bromo‐phenylamino)‐quinazolin‐6‐yl]‐acryl[ 11 C]amide [ 11 C]12da was obtained within 47 min from end of bombardment (specific activity of 60 GBq µmol −1 ). This strategy is an example of how [ 11 C]carbon monoxide can be utilised in the labelling of libraries of drug candidates and positron emission tomography tracers for in vitro and in vivo testing.