title: Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]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).
authors.affiliation: Departments of Radiology, Pediatrics, Surgery and Medicine, and School of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ganesan.v@duke.edu
authors.forename: G
authors.initials: G
authors.lastname: Vaidyanathan
authors.forename: D J
authors.initials: DJ
authors.lastname: Affleck
authors.forename: C M
authors.initials: CM
authors.lastname: Cavazos
authors.forename: S P
authors.initials: SP
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Shankar
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
authors.forename: M O
authors.initials: MO
authors.lastname: Colvin
authors.forename: M R
authors.initials: MR
authors.lastname: Zalutsky
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D009682:Magnetic Resonance Spectroscopy; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000737:chemistry / Q000378:metabolism*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: C417987:6-(3-iodo-benzyloxy)-9H-purin-2-ylamine; C417986:6-(4-(18)fluoro-benzyloxy)-9H-purin-2-ylamine; D011687:Purines; D019853:O(6)-Methylguanine-DNA Methyltransferase