O^6-3-[131I]iodobenzylguanine: Improved Synthesis and Further Evaluation of a Potential Agent for Imaging of AlkylguanineDNA Alkyltransferase

O^6-Benzylguanine derivatives with suitable radionuclides attached to the benzyl ring are potentially useful in the noninvasive imaging of the DNA repair protein, alkylguanine-DNA alkyltransferase (AGT). Previously, O^6-3-[131I]iodobenzylguanine ([131I]IBG) was prepared using a two-step approach; we now report its synthesis in a single step by the radioiododestannylation of O^6-3-(trimethylstannyl)benzylguanine in 85-95% radiochemical yield. The in vitro specific uptake of [131I]IBG in DAOY human medulloblastoma cells, in TE-671 human rhabdomyosarcoma cells and a CHO cell line transfected to express AGT was linear (r^2 = 0.9-1.0) as a function of cell density. After intravenous injection of [131I]IBG in athymic mice bearing TE-671 xenografts, tumor uptake was 1.38 +- 0.34% ID/g at 0.5 h and declined at 2 and 4 h. Preadministration of O^6-(3-iodobenzyl)guanine (IBG) at 0.5 h increased uptake not only in tumor but also in several normal tissues. Notable exceptions were thyroid (p < 0.05), lung (p <0.05) and stomach. After intratumoral injection of [131I]IBG in the same xenograft model, the uptake in tumors that were depleted of AGT by BG treatment (165.8 +- 27.5% ID/g) was about 60% of that in control mice (272.4 +- 48.2% ID/g; p < 0.05).