Richmond J. Baker

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.

A study of technegas employing X-ray photoelectron spectroscopy, scanning transmission electron microscopy and wet-chemical methods

SummaryScanning transmission electron microscopy (STEM), coupled with energy dispersive X-ray analysis (EDS), X-ray photoelectron spectroscopy (XPS) or radionuclear chemical methods, indicates that the active agent in Technegas is either polymeric TcO2 [i.e. (TcO2)n] or (TcO2)n bound to a carbon nanoparticle. The particle size observed using STEM is in good agreement with other published results. XPS has also been used to investigate technetium residues remaining on spent crucibles. The chemical form of technetium in this residue is quite different to the form detected in the aerosol particles. We conclude that the small fraction that migrates into the crucible framework upon resistive heating is reduced to either metallic technetium or carbidic forms, with the remaining nuclide evaporating as (TcO2)n with or without carbon before complete reduction can occur.

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.

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.

99mTc-imidodiphosphate — A better tracer for infarct-avid imaging

A new radiotracer, 99mTc-imidodiphosphate, has been investigated in a series of 101 consecutive admissions to a Coronary Care Unit in a large teaching hospital to assess its potential as an acute myocardial infarct imaging agent. This agent shows high sensitivity for transmural infarction (0.96), subendocardial infarction (0.88) and high overall specificity (1.00). The clarity of the images produced, and the time after the acute episode when studies were positive suggest that it is the agent of choice for imaging the acutely infarcted myocardium.