Design of CNS receptor imaging agents based on organometallic Tc(III) and Tc(I) complexes

There is a considerable interest in the development of ^99mTc radiopharmaceuticals for imaging serotonergic CNS receptors using single-photon emission tomography (SPET). To date most Tc compounds assigned as CNS receptor targeted agents are square-pyramidal complexes of the oxo ion [Tc=O]³⁺. However, the in vivo behaviour of such complexes are strongly influenced by the quite polar Tc=O unit offering a free position trans to the oxo ligand for further reaction in vivo. To reduce this in vivo reactivity, oxo-free Tc complexes containing the metal in lower oxidation states are considered to be appropriate alternatives.
Tc(III) mixed-ligand complexes (1) with tetradentate/monodentate NS₃/isonitrile coordination appear suitable to wrap the metal well in a molecule with receptor-targeting functionality. The here introduced compounds contain a methoxyphenyl-piperazine moiety derived from the selective 5-HT_1A receptor antagonist WAY 100,635 linked to the Tc chelate unit via an alkyl chain [1].

The low-pressure synthesis of a Tc-carbonyl precursor as inaugurated by Alberto et al. allows a convenient exploitation of the potential of the "Tc(CO)₃" moiety in the design of receptor-binding agents [2]. A bidentate N-donor anchor group has been considered well suitable for combining the Tc(I) tricarbonyl center with the antagonist moiety (2). Alternatively, a bidentate thioether group to link the Tc(I) tricarbonyl center with 4,7-dithiaoctanoic acid (3beta-(4-fluorophenyl)tropane-2beta)-methyl ester (3) as receptor-targeting moiety has been chosen [3].
We report the synthesis, in vitro receptor affinity and biodistribution of three candidates in order to demonstrate the suitability of the concept and to elucidate the influence of the building blocks on the biobehaviour of the complexes.