Synthesis of radiolabeled O⁶‐benzylguanine derivatives as new potential PET tumor imaging agents for the DNA repair protein O⁶‐alkylguanine‐DNA alkyltransferase

Abstract

Novel radiolabeled O6‐benzylguanine derivatives, 2‐amino‐6‐O‐[11C]‐[(methoxymethyl)benzyloxy]‐9‐benzyl purines ([11C]p‐O6‐AMBP, 1a; [11C]m‐O6‐AMBP, 1b; [11C]o‐O6‐AMBP, 1c), have been synthesized for evaluation as new potential positron emission tomography (PET) tumor imaging agents for the DNA repair protein, O6‐alkylguanine‐DNA alkyltransferase (AGT). The appropriate precursors for radiolabeling were obtained in three steps from starting material 2‐amino‐6‐chloropurine with moderate to excellent chemical yields. Tracers were prepared by O‐[11C]methylation of hydroxymethyl precursors using [11C]methyl triflate. Pure target compounds were isolated by solid‐phase extraction (SPE) purification procedure in 45–60% radiochemical yields (decay corrected to the end of bombardment), and a synthesis time of 20–25min. Copyright © 2002 John Wiley & Sons, Ltd.

Lipophilicity coefficients of potential tumor imaging agents, positron‐labeled O6‐benzylguanine derivatives

“…the parent compound O 6 -BG, in vitro AGT oligonucleotide assay was performed in our previous works (Zheng et al, 2002(Zheng et al, , 2003Liu et al, 2003a,b). Briefly, MCF-7 or HeLa cells (control) were cultured in Dulbecco's modified Eagle's medium (DME) supplemented with 10% bovine calf serum.…”

“…These results were not unexpected, because none of the O 6 -BG derivatives have been reported to be more potent AGT inhibitors than O 6 -BG (Zheng et al, 2002). However, O 6 -BG is unable to serve as a PET imaging agent for AGT, since The correlations between lipophilicity and biological properties of selected lead O 6 -BG analogs (1-3a) are shown in Table 7.…”

“…These log P values will be compared, and correlations between lipophilicity and biological activity of selected analogs will be made. works (Zheng et al, 2002(Zheng et al, , 2003Liu et al, 2003a,b). Briefly, 2-amino-6-chloropurine (ACP) was reacted directly with benzyl alcohol sodium alkoxide through a displacement reaction to give O -AMMP, 2c.…”

“…-alkylguanine-DNA alkyltransferase (AGT) in cancers (Zheng et al, 2002(Zheng et al, , 2003Liu et al, 2003a,b). The ability of O 6 -BG analogs to penetrate the blood-brain barrier (BBB) in brain tumor could be due, at least in part, to their lipophilicity (Rubenstein et al, 2001 -BG derivatives have the same retention time in HPLC chromatograms and the same lipophilicity coefficient (log P) determined by HPLC.…”

Synthetic Strategies Towards O6-Substituted Guanine Derivatives and their Application in Medicine

“…In 2002 Zheng et al [38] published the synthesis of carbon-11 and fluorine-18 radiolabeled O 6 -benzylguanine derivatives as imaging agents for AGT. The synthetic pathway described was also published in slightly modified form in another journal [39].…”