O6-3-[131I]iodobenzylguanine: improved synthesis and further evaluation of a potential agent for imaging of alkylguanine-DNA 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-[(131)I]iodobenzylguanine ([(131)I]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 [(131)I]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 [(131)I]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 [(131)I]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).
Vaidyanathan
Ganesan
G
Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, USA. ganesan.v@duke.edu
Affleck
Donna J
DJ
Norman
Joseph
J
Welsh
Phil
P
Liu
Wenge
W
Johnson
Stewart P
SP
Friedman
Henry S
HS
Zalutsky
Michael R
MR
D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D007462:Iodobenzenes / Q000138:chemical synthesis* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D006147:Guanine; C008449:O-(6)-methylguanine; C031905:iodobenzene; D019853:O(6)-Methylguanine-DNA Methyltransferase