title: Synthesis and biologic evaluation of a radioiodinated quinazolinone derivative for enzyme-mediated insolubilization therapy.
abstract: We have developed a new strategy that aims to concentrate therapeutic radionuclides within solid tumors. This approach, which we have named EMIT (enzyme-mediated insolubilization therapy), is a method for enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule (from a water-soluble precursor) within the extracellular space of solid tumors. The prodrug, ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone, labeled with iodine-125 ((125)IPD) and its authentic compound labeled with iodine-127 (IPD) have been synthesized, purified, and characterized. The alkaline phosphatase (ALP)-mediated conversion of these water-soluble nonfluorescent prodrugs to the water-insoluble fluorescent species, iodine-125-labeled 2-(2'-hydroxyphenyl)-6-iodo-4-(3H)-quinazolinone ((125)ID) and its iodine-127-labeled derivative (ID), has been demonstrated in vitro. Biodistribution studies in mice indicate that both (125)IPD and (125)ID are minimally retained by most tissues and organs. In addition, following its intravenous injection in mice, (125)IPD is localized in ALP-rich regions and converted to (125)ID, which remains indefinitely within the tissues where it is produced. We believe that EMIT is a strategy that will lead to the active and specific concentration and entrapment of therapeutic radionuclides within solid tumors, the consequent protracted irradiation of tumor cells within the range of the emitted particles, and the effective therapy of solid tumors.
authors.affiliation: Department of Radiology, Harvard Medical School, Goldenson Building B-242, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Nan-hui
authors.initials: NH
authors.lastname: Ho
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Harapanhalli
authors.forename: Bassam A
authors.initials: BA
authors.lastname: Dahman
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Ketai
authors.initials: K
authors.lastname: Wang
authors.forename: S James
authors.initials: SJ
authors.lastname: Adelstein
authors.forename: Amin I
authors.initials: AI
authors.lastname: Kassis
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism*; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D005453:Fluorescence; D007457:Iodine Radioisotopes; D051379:Mice; D009928:Organ Specificity; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000737:chemistry*; D052999:Quinazolinones; D012680:Sensitivity and Specificity; D012995:Solubility
chemical_list: D007457:Iodine Radioisotopes; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D011799:Quinazolines; D052999:Quinazolinones; C460023:ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone; D000469:Alkaline Phosphatase