title: The retention mechanism of technetium-99m-HM-PAO: intracellular reaction with glutathione.
abstract: Preparations of d,l- and meso-hexamethylpropyleneamine oxime (HM-PAO) labeled with technetium-99m were added to rat brain homogenates diluted with phosphate buffer (1:10). The conversion of d,l-HM-PAO to hydrophilic forms took place with an initial rate constant of 0.12 min-1. Incubation of the brain homogenate with 2% diethyl maleate for 5 h decreased the homogenate's measured glutathione (GSH) concentration from 160 to 16 microM and decreased the conversion rate to 0.012 min-1. Buffered aqueous solutions of glutathione rapidly converted the HM-PAO tracers to hydrophilic forms having the same chromatographic characteristics as found in the brain homogenates. The rate constant for the conversion reaction of d,l-HM-PAO in GSH aqueous solution was 208 and 317 L/mol/min in two different assay systems and for meso-HM-PAO the values were 14.7 and 23.2 L/mol/min, respectively. Rat brain has a GSH concentration of about 2.3 mM and the conversion of the d,l-HM-PAO due to GSH alone should proceed with a rate constant of 0.48 to 0.73 min-1 and be correspondingly 14-fold slower for meso-HM-PAO. In human brain, the in vivo data of Lassen et al. show a conversion rate constant of 0.80 min-1. This correspondence of values supports the notion that GSH may be important for the in vivo conversion of 99mTc-labeled HM-PAO to hydrophilic forms and may be the mechanism of trapping in brain and other cells. A kinetic model for the trapping of d,l- and meso-HM-PAO in tissue is developed that is based on data of GSH concentration in various organs.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharmaceuticals R and D, Amersham International PLC, Bucks, U.K.
authors.forename: R D
authors.initials: RD
authors.lastname: Neirinckx
authors.forename: J F
authors.initials: JF
authors.lastname: Burke
authors.forename: R C
authors.initials: RC
authors.lastname: Harrison
authors.forename: A M
authors.initials: AM
authors.lastname: Forster
authors.forename: A R
authors.initials: AR
authors.lastname: Andersen
authors.forename: N A
authors.initials: NA
authors.lastname: Lassen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005978:Glutathione / Q000493:pharmacokinetics*; D008297:Male; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D010091:Oximes / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013667:Technetium / Q000493:pharmacokinetics*; D019690:Technetium Tc 99m Exametazime
chemical_list: D009942:Organometallic Compounds; D010091:Oximes; D019690:Technetium Tc 99m Exametazime; D013667:Technetium; D005978:Glutathione