Abstract
Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).
Highlights
Approved nucleoside analogues occupy a unique place in drug therapy due to their ability to interfere in biosynthetic and metabolic pathways fundamental to aberrant cellular replication and growth
Our group has previously reported the synthesis of a series of FLT ProTides that showed a relatively safe toxicological profile compared to the parent nucleoside as well as moderate anti-HIV activity [17]
The radiochemical synthesis of [18 F]FLT ProTide (1) was planned taking into account the short half-life of fluorine-18 (110 min), with the [18 F]fluorination occurring at a late stage in the synthesis (Scheme 1)
Summary
Approved nucleoside analogues occupy a unique place in drug therapy due to their ability to interfere in biosynthetic and metabolic pathways fundamental to aberrant cellular replication and growth. This is apparent in conditions such as cancer [1] and viral infections [2], where nucleoside analogues are able to inhibit essential human or viral enzymes such as thymidylate synthase or ribonucleotide reductase. Nucleosides require activation via (normally) three successive enzyme-mediated phosphorylation steps (Figure S1) [4].
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