title: Synthesis and characterization of a C6 nucleoside analogue for the in vivo imaging of the gene expression of herpes simplex virus type-1 thymidine kinase (HSV1 TK).
abstract: The synthesis and biological evaluation of '6-(1,3-dihydroxyisobutyl)thymine' (DHBT; 1), which corresponds to 6-[3-hydroxy-2-(hydroxymethyl)propyl]-5-methylpyrimidine-2,4(1H,3H)-dione, is reported. DHBT (1) was designed as a new substrate for herpes simplex virus type-1 thymidine kinase (HSV1 TK). The compound was found to be exclusively phosphorylated by HSV1 TK, and to exhibit good binding affinity (Ki = 35.3+/-1.3 microM). Cell-proliferation assays with HSV1-TK-transduced human osteosarcoma cells (143B-TK+-HSV1-WT) and with both human-thymidine-kinase-1-negative (143B-TK-) and non-transduced parental (MG-63) cells indicate that 1 is less cytotoxic than the standard drug Ganciclovir. Thus, DHBT (1) represents a promising precursor of a nontoxic reporter probe for the monitoring of HSV1 TK gene expression by means of positron-emission tomography (PET).
authors.affiliation: Center for Radiopharmaceutical Science of the ETH, PSI, USZ, and D-CHAB, ETH Hönggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich.
authors.forename: Anass
authors.initials: A
authors.lastname: Johayem
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
authors.forename: Katia
authors.initials: K
authors.lastname: Lazzati
authors.forename: Pius A
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics
chemical_list: D009705:Nucleosides; D013937:Thymidine Kinase