Radiolabeled Guanine Derivatives for the in Vivo Mapping of O⁶-Alkylguanine-DNA Alkyltransferase:  6-(4-[¹⁸F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[¹³¹I]Iodo-benzyloxy)-9H-purin-2-ylamine

Abstract

Two radiolabeled analogues of 6-benzyloxy-9H-purin-2-ylamine (O(6)-benzylguanine; BG) potentially useful in the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase (AGT) were synthesized. Fluorine-18 labeling of the known 6-(4-fluoro-benzyloxy)-9H-purin-2-ylamine (FBG; 6) was accomplished by the condensation of 4-[(18)F]fluorobenzyl alcohol with 2-aminopurin-6-yltrimethylammonium chloride (4) or 2-amino-6-chloropurine in average decay-corrected radiochemical yields of 40 and 25%, respectively. Unlabeled 6-(3-iodo-benzyloxy)-9H-purin-2-ylamine (IBG; 7) was prepared from 4 and 3-iodobenzyl alcohol. Radioiodination of 9, prepared from 7 in two steps, and subsequent deprotection gave [(131)I]7 in about 70% overall radiochemical yield. The IC(50) values for the inactivation of AGT from CHO cells transfected with pCMV-AGT were 15 nM for IBG and 50 nM for FBG. The binding of [(18)F]6 and [(131)I]7 to purified AGT was specific and saturable with both exhibiting similar IC(50) values (5-6 microM).

A Design of Experiments (DoE) Approach Accelerates the Optimization of Copper-Mediated 18F-Fluorination Reactions of Arylstannanes

“…In this case, deviations from the predicted model may be due to factors such as the amount of carbonate base present in the in larger volumes of QMA eluent solution (as discussed above), effects from as of yet unidentified controllable or non-controllable factors specific to this reaction, and/or model/data inaccuracies obtained through either random or systematic experimental error. Nonetheless, this easily automatable procedure mitigated the product losses sustained using the previously published 2-step synthesis approach 32 .…”

“…The synthesis [ 18 F] p FBnOH [ 18 F]6 , an important radiochemical building block, has also been of interest to a number of projects within our laboratory. [ 18 F]6 has been previously synthesized in two steps via the nucleophilic aromatic substitution of 4-formyl- N,N,N -trimethylanilinium triflate and the subsequent reduction of the resulting 4-[ 18 F]fluorobenzaldehyde to [ 18 F]6 32,33 . In our hands the reduction step using NaBH 4 resulted in a significant loss of the product [ 18 F]6 and we thus chose to investigate the CMRF of 4-tributyltinbenzyl alcohol 5 as a possible single-step alternative route to [ 18 F]6 (Fig.…”

Synthesis and Biological Activity of Novel 6-Substituted Purine Derivatives

“…The purine derivatives are of great importance to chemists as well as to biologists as they have been found in a large variety of naturally occurring compounds and also in clinically useful molecules having diverse biological activities [1,2]. Purine bases modified in the 6-position and their derivatives and analogues possess a wide range of biological properties such as antitubercular, fungicidal, antiallergic, antimicrobial, antitumor, antihistamic, myocardium inhibiting agent, etc [3][4][5][6][7][8][9][10][11][12][13][14].…”

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

“…Therefore, the ability of tumor cells to be resistant to toxic effects of alkylating agents is dependent on cellular AGT levels; the higher the AGT content, the less effective will be tumor killing by alkylator therapy. 2 Tumor cells frequently express high levels of AGT. Human AGT is encoded by the O 6 -methylguanine-DNA methyltransferase (MGMT) gene.…”