Synthesis and tumor uptake of 5-/sup 82/Br- and 5-/sup 131/I-labeled 5-halo-1-(2-fluoro-2-deoxy-beta-D-ribofuranosyl)uracils

Journal Article · Thu Jun 01 00:00:00 EDT 1989 · J. Med. Chem.; (United States)

DOI:https://doi.org/10.1021/jm00126a024· OSTI ID:5767047

Mercer, J R; Xu, L H; Knaus, E E; Wiebe, L I

A synthesis of 5-bromo- and 5-iodo-1-(2-fluoro-2-deoxy-beta-D-ribofuranosyl)uracil (3 and 4) and their 5-/sup 82/Br and 5-/sup 131/I analogues has been developed. The tissue distribution of the radiolabeled compounds in BDF1 mice bearing Lewis lung tumors has been investigated. After injection of the radiolabeled analogues of compounds 3 and 4 there was a rapid initial excretion of activity. Compound 3 was excreted unchanged in the urine. Residual activity in mice after 4 h showed a distribution characteristic of bromide (Br-). Compound 4 was excreted mainly as unchanged starting material with increasing amounts of iodide (I-) detected at later time periods, in addition to 5-iodouridine and unidentified metabolites at shorter time periods. Both 3 and 4 demonstrated a remarkable in vivo stability relative to related 5-substituted nucleosides that do not contain the 2'-fluoro group. The tumor uptake was minimal, with only the 5-bromo analogue demonstrating a slight elevation in tumor to blood ratios relative to other tissues. Compounds 3 and 4 were shown to compete with thymidine for the same binding site in the transport of nucleosides across the cell membrane in mouse erythrocytes. The inhibition constants (Ki) show that the compounds were weak competitors of thymidine binding to pyrimidine nucleoside transporter compared to physiological nucleosides. Other evidence indicates that compounds 3 and 4 are not substrates for mammalian kinase enzymes.

• Research Organization: Univ. of Alberta, Edmonton (Canada)
• OSTI ID: 5767047
• Journal Information: J. Med. Chem.; (United States), Vol. 32:6
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
LUNGS
NEOPLASMS
RADIOPHARMACEUTICALS
UPTAKE
BROMINE 82
CHEMICAL PREPARATION
COMPARATIVE EVALUATIONS
DNA
FUDR
IODINE 131
LABELLING
MEMBRANE TRANSPORT
MICE
MOLECULAR STRUCTURE
STRUCTURE-ACTIVITY RELATIONSHIPS
THYMIDINE
TISSUE DISTRIBUTION
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIMETABOLITES
ANTIMICROBIAL AGENTS
AZINES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BODY
BROMINE ISOTOPES
DAYS LIVING RADIOISOTOPES
DISEASES
DISTRIBUTION
DRUGS
FLUOROURACILS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INTERMEDIATE MASS NUCLEI
IODINE ISOTOPES
ISOTOPES
LABELLED COMPOUNDS
MAMMALS
NUCLEI
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ODD-EVEN NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANIC FLUORINE COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRIMIDINES
RADIOISOTOPES
RESPIRATORY SYSTEM
RIBOSIDES
RODENTS
SYNTHESIS
URACILS
VERTEBRATES
550601* - Medicine- Unsealed Radionuclides in Diagnostics