Johan C. Bellen

Paramagnetic Complexes of Manganese(II), Iron(III), and Gadolinium(III) as Contrast Agents for Magnetic Resonance Imaging: The Influence of Stability Constants on the Biodistribution of Radioactive Aminopolycarboxylate Complexes

Paramagnetic complexes of manganese(II), iron(III), and gadolinium(III) with many ligands appear to undergo ligand substitution in vivo, producing biodistribution data similar to the hydrated metal ions. To identify ligands likely to be valuable in the preparation of paramagnetic contrast agents, a series of aminopolycarboxylate complexes with stability constants increasing in the order iminodiacetic acid (IDA) less than nitrilotriacetic acid (NTA) less than EDTA less than CDTA less than or equal to DTPA was prepared with 54Mn(II), 59Fe(III), and 153Gd(III) at both tracer and carrier levels. Biodistribution studies in mice suggested that complexes remained unchanged in vivo if their stability constants (K1) were approximately greater than 10(16) for Mn(II) and Gd(III) and greater than 10(22) for Fe(III) complexes at tracer levels. Metal complexes with added carrier appeared to be effectively more stable in vivo, possibly due to dissociation and saturation of metal-binding sites. To avoid the accumulation of metal ions in tissues, new paramagnetic contrast agents containing these metal ions will require stability constants equal to or greater than those identified here.

Radiolabeling and biodistribution of amiodarone and desethylamiodarone.

The antiarrhythmic drug amiodarone and its metabolite desethylamiodarone, were radiolabeled with sodium [123I]-iodide in > 98% yield using the exchange labeling method. Biodistribution studies with 123I-amiodarone in mice showed high liver and lung uptake. Heart uptake of 0.98% of the injected dose (id) peaked at 5 min, with clearance seen over 60 min to 0.44% id. 123I-Desethylamiodarone (123I-DEA) showed heart uptake of 0.58% id peaking at 5 min, with slower clearance seen over 60 min to 0.43% id. These results indicate that both agents have poor selectivity as myocardial imaging tracers. Low 123I-DEA brain uptake at 5 min (0.49% id) and rapid washout after 60 min indicate that 123I-desethylamiodarone has limited application as a brain imaging agent.

The Preparation of 99mTc—Tertiarybutylisonitrile (99mTc-TBI) by a method suitable for routine clinical use

The myocardial imaging agent technetium-99m-hexakis (tertiarybutylisonitrile) (99mTc-TBI) was prepared by the reaction of [99mTc]pertechnetate with TBI in 50% ethanol/0.9% saline at 100 degrees C, using stannous chloride as the reducing agent. A study of the reaction parameters enabled the yield to be optimized to better than 90%, although this was reduced to approximately 60% if a purification step was carried out. Chromatographic analysis on ITLC-SG medium showed the final product to be of high radiochemical purity. Biological studies comprising biodistribution in mice over a 2-h period, imaging studies in animals and sub-acute toxicity testing in mice indicated that 99mTc-TBI prepared as here described is a suitable agent for routine clinical use in humans.

Radiochemical characterization of modified technegas

The aim of this study was to characterize modified Technegas, employing radiochemical analyses and qualitative rabbit organ imaging techniques. Electrophoresis, thin layer chromatography and imaging studies, found modified Technegas to behave like sodium [99mTc]pertechnetate (pertechnetate). Our data indicate that modified Technegas is a pertechnetate aerosol, which results from the presence of 3% oxygen in the reaction atmosphere of the Technegas generator.

Studies of 99mTc-acylplasmins as agents for thrombus detection

It has been proposed that acylation at the active site of plasmin is able to prevent its reaction with α2-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.

The effect of lipophilic substituents on the biological properties of EDTA complexes containing paramagnetic metal ions

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.

A comparison of radiolabelled agents for thrombus imaging using a rabbit model

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.