ABSTRACT
Complexes of the radioactive paramagnetic metal ions 51Cr(III), 54Mn(II), 59Fe(III), 57Co(II), 64Cu(II) and 153Gd(III) were prepared with EDTA and its derivative containing the lipophilic 1-(4-methylphenyl)-group (MPEDTA), together with the corresponding 99mTc-compounds. The formation of these complexes was verified by electrophoresis and they were screened for potential use as MRI hepatobiliary contrast agents by biodistribution studies in mice. In this series, the MPEDTA complexes of 54Mn(II) and 64Cu(II) showed increased urinary excretion compared to the unsubstituted EDTA complexes, while the MPEDTA complexes of 99mTc, 59Fe, 57Co, 153Gd and particularly 51Cr demonstrated improved hepatobiliary excretion. Further lipophilic substitution should enhance this property but the preparation of such ligands is complicated by cyclisation reactions.
Subject(s)
Edetic Acid/metabolism , Metals/metabolism , Animals , Female , Kinetics , Mice , Mice, Inbred BALB C , Radioisotopes , Tissue DistributionABSTRACT
The quantitative uptakes of five potential thrombus-localizing radiopharmaceuticals in experimental thrombi of the rabbit jugular vein have been compared to assist with the selection of a thrombus imaging agent for clinical use. Three hours after injection, 111In-platelets were clearly the agent of choice but at 18 h 99mTc-fibrinogen had more favourable characteristics. Both agents were superior to 99mTc-plasmin or its acyl derivatives, including 99mTc-streptokinase-activated anisoylplasminogen. The ease of preparation coupled with favourable biological properties suggest that 99mTc-fibrinogen should be of value in the clinical situation.
Subject(s)
Jugular Veins/diagnostic imaging , Organometallic Compounds , Thrombosis/diagnostic imaging , Animals , Indium , Iodine Radioisotopes , Oxyquinoline/analogs & derivatives , Rabbits , Radionuclide Imaging , TechnetiumABSTRACT
It has been proposed that acylation at the active site of plasmin is able to prevent its reaction with alpha 2-antiplasmin without affecting the fibrin affinity of the enzyme. To investigate the possibility that 99mTc-labelled acylplasmins are improved thrombus-detecting agents, six acylating agents were synthesised and their reaction with plasmin and the labelling of the products with 99mTc studies. Uptake of 99mTc-acylplasmins in an in vitro thrombus model was complicated by precipitation processes, which may in part account for the rapid blood clearance in rabbits and high liver uptake in mice injected with the compounds. Quantitative measurements using an in vivo rabbit thrombus model demonstrated that guanidinobenzoyl-plasmin exhibited nearly a threefold increase in thrombus uptake compared with non-acylated 99mTc-plasmin. The observed uptake is less than that obtained with 125I-fibrinogen at clinically useful time intervals post-injection but represents a significant advantage over the use of 99mTc-plasmin.
Subject(s)
Organotechnetium Compounds , Thrombosis/diagnostic imaging , Acylation , Animals , Female , Fibrinolysin/metabolism , Humans , In Vitro Techniques , Metabolic Clearance Rate , Mice , Rabbits , Radionuclide Imaging , Technetium/metabolism , Thrombosis/metabolismABSTRACT
Deacylation rate constants, k3, were measured for the human acyl-plasmins which contain in the acyl portion, RCO, the R groups methyl, cyclohexyl, p-nitrophenyl, isobutyl, trans-isopropenyl, phenyl, alpha-naphthyl, anisoyl and p-guanidinophenyl. Values of k3 were also determined for the porcine acyl-plasmins which have R = methyl, cyclohexyl, phenyl, anisoyl and p-guanidinophenyl. In general, for both the human and porcine acyl-plasmins, k3 decreased as the electron-donating ability of the acyl group increased. At 25 degrees C, the human acyl-plasmin with R = methyl has the highest k3, 1.06 +/- 0.05 X 10(-2) s-1, and the porcine acyl-plasmin with R = p-guanidinophenyl the lowest k3, 1.4 +/- 0.1 X 10(-6) s-1.
