Synthesis of [¹⁸F]‐labeled N‐3(substituted) thymidine analogues: N‐3([¹⁸F]fluorobutyl) thymidine ([¹⁸F]‐FBT) and N‐3([¹⁸F]fluoropentyl) thymidine ([¹⁸F]‐FPT) for PET

Abstract

1,4-Butane diol and 1,5 pentane diol were converted to their tosyl derivatives 2 and 3 followed by conversion to benzoate esters 4 and 5, respectively. Protected thymidine 1 was coupled separately with 4 and 5 to produce 6 and 7, which were hydrolyzed to 8 and 9, then converted to their mesylates 10 and 11, respectively. Compounds 10 and 11 were fluorinated with n-Bu 4 N[18 F] to produce 12 and 13, which by acid hydrolysis yielded 14 and 15, respectively. The crude products were purified by HPLC to obtain [ 18 F]-FBT and [ 18 F]-FPT. The radiochemical yields were 58-65% decay corrected (d.c.) for 14 and 46-57% (d.c.) for 15 with an average of 56% in three runs per compound. Radiochemical purity was >99% and specific activity was >74 GBq/mmol at the end of synthesis (EOS). The synthesis time was 65-75 min from the end of bombardment (EOB).

N3-Substituted Thymidine Bioconjugates for Cancer Therapy and Imaging

“…These studies primarily focused on the design, synthesis and biological evaluation of thymidine analogues with radiolabels at the N3-postion for cancer therapy and imaging (Figures 16 & 17). Alauddin et al reported the synthesis of a library of compounds with chloro-, bromo-, and iodo-substitutions at various positions of a N3-phenylalkyl side chain at thymidine (79–81) [86]. These agents may have been synthesized in preparation of a later synthesis of their radiohalogenated counterparts.…”

“…Relative TK1 phosphorylation rates for some compounds of this series ranged from 2–6% [26]. Members of the research teams of Toyohara, Alauddin and Balzarini synthesized and evaluated several analogues with 18 F or 19 F attached to N3-alkyl side chains (82–87) [27,28,86–89,101]. Balzarini et al observed that 83 was a relatively poor inhibitor of thymidine phosphorylation by TK1 [28].…”

Nucleoside‐based probes for imaging tumor proliferation using positron emission tomography

“…An unnatural analog of FMAU, [ 18 F]‐ l ‐FMAU, was recently developed and was shown to have efficacy in PET imaging of tumor proliferation . N 3 ‐Substitued TdR analogs have been synthesized, radiolabeled, and studied in limited experiments …”

“…A number of N 3 ‐substitued TdR analogs have been synthesized and radiolabeled with 18 F to assess their efficacy for PET imaging of tumors . Previously, a series of N 3 ‐substituted TdR analogs carrying a carboranylalkyl moiety at the N 3 ‐position with various spacer lengths was developed and drew attention in boron neutron capture therapy .…”

“…Previously, a series of N 3 ‐substituted TdR analogs carrying a carboranylalkyl moiety at the N 3 ‐position with various spacer lengths was developed and drew attention in boron neutron capture therapy . This prompted scientists to synthesize [ 18 F] N 3 ‐substituted TdR analogs for PET imaging . Figure B shows the radiosynthesis of the N 3 ‐substituted TdR analogs with the [ 18 F]‐containing straight chain at the N 3 ‐position.…”