Abstract
Abstract A new, high radiochemical yield synthesis of [18F]FHBG and [18F]FHPG, the most popular imaging agents currently in use for monitoring gene therapy using positron emission tomography (PET), is reported in this work. Protection of sensitive sites in the precursors generally utilized for the preparation of [18F]FHBG and [18F]FHPG using the nucleophilic 18F-fluorination reaction was found to be critical for good radiochemical yields, reliability and reproducibility of the synthetic process. As an initial approach, protection at O6-oxygen in the guanine moiety of the currently used monomethoxytrityl-protected penciclovir tosylate derivative 9 with carbamoyl groups was carried out. Subsequently, full protection of both O6-oxygen and N2-nitrogen in the monomethoxytrityl-protected penciclovir and ganciclovir tosylate analogs 9 and 10 were achieved by their reaction with di-tert-butyl dicarbonate, which resulted in O6-tert-butyl-N2-Boc-monomethoxytrityl-protected penciclovir tosylate 18 and O6-tert-butyl-N2-Boc-monomethoxytrityl-protected ganciclovir tosylate 19, respectively. The newly synthesized carbamoyl- and the Boc- protected precursors were first reacted with non-radioactive KF complexed with Kryptofix 222 to isolate the fluorinated products. Acid hydrolysis of the purified fluorinated intermediates provided the nucleosides FHBG and FHPG. Full characterization of the new precursors as well as the products obtained by fluorination and hydrolysis reactions were carried out by one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Single crystal X-ray crystallographic analysis of a model ganciclovir analog 22 confirmed the structural characterization of the new Boc-protected tosylate precursors 18 and 19 by NMR spectroscopy. The carbamoyl- and the Boc-protected precursors were further subjected to radiofluorination followed by acid hydrolysis reactions to furnish [18F]FHBG and [18F]FHPG reliably and reproducibly in excellent radiochemical yields (>65%), much higher than those previously achieved.
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