Derivatization strategies of small biomolecules for the labeling with the organometallic "^99mTc(CO)₃"-core

Small, radiolabeled biomolecules, such as steroids, tracers for the central nervous system and biotin obtained considerable attention in diagnostic nuclear medicine. Nowadays, there are numerous short living isotopes available for SPECT (e.g. ¹³¹I) and PET (e.g. ¹⁸F, ¹¹C) imaging to label such biological vectors. Despite this fact. Tc-99m is still the isotope of choice for diagnostic purpose because of its ideal decay properties. However, unlike iodinated of fluorinated radiopharmaceuticals, Tc-99m requires a highly sophisticated functionalization and coordination chemistry. Attempts to substitute direct covalent bound isotopes by Tc-99m chelates were, apart from peptides, only partially successful. (1,2) The reason is mainly the size of the introduced chelates (interference with active site of the biomolecule) and the redox sensitivity of ^99mTc in the oxidation state +3 and +5. Therefore, alternative approaches are required to overcome these problems by introduction of small, redox inert ^99mTc-cores in combination with simple ligand systems.
Although the idea of labeling e.g. steroids with organometallic Re or Tc-compounds was published by Top et al. In 1995 the attempt failed due to synthetic problems of the precursor on the no-carrier added level.(3) Our group recently pioneered the synthesis of the organometallic Tc(I) complex fac-[M(OH₂)₃(CO)₃]⁺ (M=^99mTc 1a, ⁹⁹Tc 1b, Re 1c) under safe and pressureless conditions in aqueous media in high yields (<95%).(4,5) The compound is characterized by its water solubility, pronounced kinetic inertness (low spin d⁶ system) and the substitution lability of the three coordinated water molecules enabling effective labeling under mild conditions. The small size of the organometallic center will minimize the interference with the binding side of a biomolecule. Therefore, this new label optimi ...