Development of technetium-99m-based CNS receptor ligands: have there been any advances?

By virtue of its ideal nuclear physical characteristics for routine nuclear medicine diagnostics and its ready availability, technetium-99m (^99mTc) is of outstanding interest in the development of novel radiopharmaceuticals. The potential of developing ^99mTc-based radioligands also for studying the receptor function in the central nervous system (CNS) is well recognized despite the difficulties to be overcome. A fundamental challenge is the pharmacologically acceptable integration of the transition metal technetium with its peculiar coordination chemistry into the molecular entity of CNS receptor ligands. Conceptually, the ligand molecule can be assembled by three building blocks: a small neutral chelate unit, an organic linker that may also serve as pharmacological modifier and a receptor-binding region derived from selective receptor antagonists. The recent introduction of novel technetium chelate units, particularly mixed-ligand complexes and low-valency organometallic compounds of technetium, provides an impetus for the further development of CNS receptor ligands. Moreover, progress in receptor pharmacology and experience gained with PET radiotracers have facilitated the design of numerous ^99mTc-based CNS receptor ligands. The formidable challenge of developing ^99mTc probes as SPET imaging agents targeting CNS receptors can be meet with optimism in view of the successful development of [^99mTc]TRODAT-1 as a ^99mTc complex for imaging dopamine transporters in the brain, although there are a number of receptor-specific imaging agents that have so far resisted all efforts to develop them.
This review presents recent advances and discusses the remaining hurdles in the design of ^99mTc-based CNS receptor imaging agents.