Bioactivity of small technetium complexes

Early evidence that small technetium compounds may be subject to active transport processes was provided by the historical serependipitous finding that pertechnetate was handled by the sodium-iodide symporter in the thyroid gland. The pertechnetate ion can mimic the iodide ion, despite its different nature and geometry.
Starting from this observation ^99mTc radiotracers are designed for probing and imaging a distinct biochemical reaction of diagnostic relevance. Such biochemical reactions are transmembrane processes, binding reactions, enzymatic conversions, possibly redox reactions, etc., and key proteins or enzymes are the targets of the ^99mTc diagnostic agents. "Bioactivity" is therefore required in the sense of the ^99mTc species being able to participate in the biochemical reaction of interest, being bound or processed.
Keeping the artificiality of technetium in the human body in mind, the feasibility of biochemical Tc-99m probes can only be based on imperfection of the target specificity, on the tolerance of the target molecule towards a substrate mimic that accidentally fits the target molecule to some extent, despite its different chemical nature. This will be examplified by the development of ^99mTc ligands for brain receptors.
The possibility of using biochemical^99mTc probes for various CNS receptors is due to the tolerance of the target molecules towards metal-based mimics. As the high in-vitro affinities to various neuroreceptors in the nanomolar and subnanomolar range indicate, molecular recognition of complex technetium molecules has become possible.
However, one main issue in developing CNS receptor imaging agents remains the very low or totally absent brain uptake. After two decades of research into brain ^99mTc perfusion agents it has now become feasible for certain technetium complexes to cross the blood-brain barrier. In contrast, a suitable combination of a high receptor affinity with a sufficient brain uptake was not achieved. Systematic studies of model technetium compounds with various logP and pKa values provided rules for selected homologous series of complexes but did not really help to tackle the problem. Since a wide variety of chemically diverse compounds, among them lipophilic cations such as ^99mTc MIBI, ^99mTc tetrofosmin or Q-series compounds, may be actively transported out of the cell by P-glycoprotein, it might also affect the transport of potentially receptor-binding ^99mTc agents.

To conclude, approaches to specific small technetium radiopharmaceutical tracers have not changed much in recent years. From a coordination chemistry point of view, the design of new ^99mTc radiopharmaceuticals starts conceptually with the modification of the coordination environment around the metal with a variety of chelators. Diversity of the chelate unit is needed, and considerable research has consequently been devoted to designing improved and new chelate types, resulting in a flourishing technetium chemistry. New impetus has come in particular from the progress made in technetium(I) chemistry.
Although this knowledge explosion in the technetium chemistry has been translated into targeted radiopharmaceutical research activity the number of newly launched Tc-99m radiopharmaceuticals is stagnant, at least in a short-term perspective. The development of biochemically specific, small technetium and rhenium complexes remains therefore a challenging, rewarding and often frustrating activity.