Synthesis of 18F- and 76Br-labelled oligonucleotide and nucleoside derivatives

Sammanfattning: With the aim of developing synthetic routes to oligodeoxynucleotides and analogues labelled with the positron-emitting radionuclides 18F and 76Br (half-lives 1.8 and 16.2 h, respectively), a number of compounds containing amine-reactive electrophiles were synthesised and used in preparation of oligodeoxynucleotide derivatives labelled in the 5´-position. Some 76Br-labelled nucleoside derivatives, which might be useful in the preparation of oligodeoxynucleotides containing a 5-[76Br]bromouracil unit, were also synthesised.The novel compounds 4-([18F]fluoromethyl)phenyl isothiocyanate and N-succinimidyl 4-[76Br]bromobenzoate were prepared in 13-15% and 45-60% isolated radiochemical yields, respectively. The previously reported N-succinimidyl [18F]fluorobenzoate was prepared by a modified procedure. The reactions of these compounds with oligodeoxynucleotides and phosphorothioate oligodeoxynucleotides (6- to 30-mers) modified in the 5´-position with a hexylamine group were investigated. With regard to chemical stability, an aromatic position of the halogen was found superior in the conditions of the oligodeoxynucleotide labelling reaction. Using the 18F- and 76Br-labelled succinimidyl esters, labelled oligodeoxynucleotidesand phosphorothioate oligodeoxynucleotides were obtained in 5-19% isolated radiochemical yield.The 76Br-labelled nucleoside 5-[76Br]bromo-2´-deoxyuridine was prepared in 60% isolated radiochemical yield. The corresponding phosphoramidite derivative 5´-O-[bis(4-methoxyphenyl)-phenylmethyI]-5-[76Br]bromo-2´-deoxyuridine 3´-[(2-cyanoethyl)-bis(1-methylethyl)phosphoramidite], was synthesised in 19-24% radio-chemical yield.