First application of the metallotricarbonyl concept to design CNS receptor imaging agents based on Technetium-99m

There has been considerable interest in the development of technetium-99m radiopharmaceuticals for imaging CNS receptors.
Apart from [^99mTc]TRODAT-1 for the dopamine transporter (1), the strategies applied so far for specific CNS radiotracers failed in the ultimate goal of providing imaging agents. Both in the integrated approach with the chelate meant to be part of the pharmacophore and the pendant approach simply attaching the chelate moiety to highly potent antagonists, the chelate unit often proved to be more crucial than initially anticipated. Although the currently available chelate units make it possible to alter and adjust overall properties such as size, shape, charge, polarity (oxo, dioxo, oxo-free) and lipophilicity, insufficient receptor affinity or negligible initial brain uptake remain an unsolved problem. The introduction of the small organometallic "Tc(CO)₃" moiety into the design of ^99mTc radiopharmaceuticals (2-4) considerably extend the versatility in designing new technetium or analogous rhenium complexes. The low-pressure synthesis of a Tc-carbonyl precursor as inaugurated by Alberto et al. (2) allows a convenient exploitation of the potential of the "Tc(CO)₃" moiety in radiotracer design. We became particularly interested in studying the suitability of the new building block for the synthesis of Tc and Re based receptor-binding agents. Based on earlier work on thioether ligands (5) we have chosen a bidentate thioether group to link the Tc(I) tricarbonyl center with a receptor-ligand moiety. In a previous work, we applied this concept already to a steroid (6). Alternatively, a bidentate N-donor anchor group has been considered well suitable for combining the Tc(I) tricarbonyl center with the antagonist moiety.
Here we report the synthesis and in vitro receptor affinity of three candidates (Fig. 1) for the 5-HT_1A receptor, 5-HT_2A receptor, and dopamine transporter, respectively, in order to demonstrate the suitability of the concept.