Synthesis and preliminary biological evaluation of radiolabeled O6-benzylguanine derivatives, new potential PET imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in breast cancer.

Abstract

Novel radiolabeled O(6)-benzylguanine (O(6)-BG) derivatives, 2-amino-6-O-[(11)C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([(11)C]p-O(6)-AMMP, 1a; [(11)C]m-O(6)-AMMP, 1b; [(11)C]o-O(6)-AMMP, 1c), 2-amino-6-O-benzyloxy-9-[(11)C]-[(methoxycarbonyl)methyl]purine ([(11)C]ABMMP, 2), and 2-amino-6-O-benzyloxy-9-[(11)C]-[(4'-methoxycarbonyl)benzyl]purine ([(11)C]ABMBP, 3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) in breast cancer. The appropriate precursors for radiolabeling were obtained in two to three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-[(11)C]methylation of hydroxymethyl or acid precursors using [(11)C]methyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45-65% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 20-25 min. The activity of unlabeled standard samples of 1-3 was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate the synthesized analogs have similar strong inhibitory effectiveness on AGT in comparison with the parent compound O(6)-BG. The results warrant further evaluation of these radiotracers as new potential PET imaging agents for the DNA repair protein AGT in breast cancer in vivo.

• Authors: Qi-Huang Zheng, Xuan Liu, Xiangshu Fei, Ji-Quan Wang, David W Ohannesian, Leonard C Erickson, K Lee Stone, Gary D Hutchins
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 30 Issue 4 Pg. 405-15 (May 2003) ISSN: 0969-8051 [Print] United States
• PMID: 12767398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzyl Compounds
• Radiopharmaceuticals
• Guanine
• Alkyl and Aryl Transferases
• DNA alkyltransferase

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Benzyl Compounds (chemical synthesis, pharmacokinetics)
• Breast Neoplasms (enzymology)
• DNA Repair (drug effects)
• Guanine (analogs & derivatives, chemical synthesis, pharmacology)
• Radiopharmaceuticals (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Tomography, Emission-Computed