Review
New directions in the coordination chemistry of 99mTc: a reflection on technetium core structures and a strategy for new chelate design

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Abstract

Bifunctional chelates offer a general approach for the linking of radioactive metal cations to macromolecules. In the specific case of 99mTc, a variety of technologies have been developed for assembling a metal–chelate–biomolecule complex. An evaluation of these methodologies requires an appreciation of the coordination characteristics and preferences of the technetium core structures and oxidation states, which serve as platforms for the development of the imaging agent. Three technologies, namely, the MAG3-based bifunctional chelates, the N-oxysuccinimidylhydrazino-nicotinamide system and the recently described single amino acid chelates for the {Tc(CO)3}1+ core, are discussed in terms of the fundamental coordination chemistry of the technetium core structures. In assessing the advantages and disadvantages of these technologies, we conclude that the single amino acid analogue chelates (SAAC), which are readily conjugated to small peptides by solid-phase synthesis methods and which form robust complexes with the {Tc(CO)3}1+ core, offer an effective alternative to the previously described methods.

Introduction

The ability to incorporate readily available radionuclides with optimal decay characteristics into tracer molecules has been the foremost consideration in developing diagnostic radiopharmaceuticals. In this respect, 99mTc has become the mainstay of diagnostic nuclear medicine and in some chemical form is used in the majority of the diagnostic scans performed each year in hospitals [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. This preferential use of 99mTc radiopharmaceuticals reflects the ideal nuclear properties of the isotope, as well as its convenient availability from commercial generator columns. 99mTc emits a 140-keV γ-ray with 89% abundance, which is close to optimal for imaging with commercial gamma cameras. The absence of tissue-damaging corpuscular radiation allows the injection of activities of more than 30 mCi with low radiation exposure to the patient [8]. The 6-h half-life is sufficiently long for pharmaceutical preparation and in vivo accumulation in the target tissue, but yet short enough to minimize radiation dose to the patient or to cause environmental repercussions. Moreover, the availability of the relatively stable 99Tc isomer allows development of technetium coordination chemistry and modeling of technetium radiopharmaceuticals [21], [22], [23], [24], [25].

However, one disadvantage of technetium chemistry is that the metal, unlike 123I or 18F, cannot directly substitute a hydrogen atom of a biomolecule, nor can other common constituents of biomolecules, such as carbon, nitrogen or oxygen, be replaced by technetium. Consequently, the design of imaging agents in general requires considerable development of the coordination chemistry of the radiometal.

Section snippets

General types of technetium radiopharmaceuticals

Technetium-based radiopharmaceuticals can be described using various criteria related to either the relevance of the technetium complexation to the overall fate of the complex (technetium-essential or technetium-tagged). Conceptually, for Tc-essential, the Tc atom completes the vector. In the case of Tc-tagged, the Tc atom rides the vector. In the case of the technetium-essential compounds, technetium imparts a particular physicochemical character to the molecule, which effectively enhances or

The coordination chemistry of technetium in the development of radiopharmaceuticals

It is noteworthy that all formal oxidation states of technetium between −I and +VII are represented by characterized compounds [57]. The most stable and readily accessible oxidation states are often characterized by chemically robust core structures, which may be exploited as platforms for the development of radiopharmaceutical reagents. Several examples of structures incorporating such core geometries are illustrated in Fig. 2. The {MO}3+ core, characteristic of Tc(V), is stabilized by

MAG3-based and related bifunctional chelates [36,107,108]

The 99mTc(V)O complex of mercaptoacetyltriglycine (MAG3H5), [TcO(MAG3H)] shown in Fig. 8 was developed by Fritzberg et al. [109] as an anionic kidney-imaging agent. The parent ligand is readily derivatized as the S-acetyl MAG3-ethyl ester, containing a p-isothiocyanatobenzyl substituent, or as the S-acetyl MAG3-hydroxysuccinimidyl ester for conjugation to biomolecules [110].

MAG3H5 is a member of the general family of NxS(4−x) chelates, which are employed for coordination to the {Tc(V)O}3+ core

The 99mTc/HYNIC system

An alternative pendant approach to radiolabeling is provided by HYNIC [119], [120], [121], [122], [123], [124], [125]. When combined with a molecule such as a protein, polypeptide or glycoprotein in neutral or slightly basic media, the protein-reactive part of HYNIC reacts with nucleophilic groups in the macromolecule, such as the ɛ-amine groups of lysine residues, to yield a conjugate containing free hydrazine/hydrazide groups, referred to as HYNIC-protein. Since we first reported the use of

Single amino acid chelators for the {Tc(I)(CO)3}1+ core

While the {Tc(V)O}3+ and the various Tc-organohydrazino cores are the most extensively studied technetium subunits for radiopharmaceutical development, other core geometries allow the introduction of a variety of novel chelators, which may influence biodistribution, sample purity and stability of the preparation. In this respect, the organometallic nature of the Tc-tricarbonyl core has brought renewed interest in the design of 99mTc radiopharmaceuticals. The Tc(I)-tricarbonyl core offers a

Concluding observations

The coordination chemistry of technetium is characterized by a range of accessible oxidation states, −I to +VII, several of which are associated robust core geometries, exploitable as platforms for the development of radiopharmaceuticals. The most extensively studied to date are the {Tc(V)O}3+ core and the Tc-organohydrazino cores. The bifunctional chelate approach to radiopharmaceutical design is represented by MAG3 and related complexes of the {Tc(V)O)3+ core and HYNIC-based conjugates for

References (186)

  • S. Seifert et al.

    Ligand-exchange reaction of labile “3+1” 99mTc(V) complexes with SH group-containing proteins

    Appl. Radiat. Isot.

    (2001)
  • T. Nicholson et al.

    Monomeric five-coordinate rhenium diazenido and hydrazido complexes with aromatic thiolate ligands: x-ray structures of [Re(NNC6H4-4-Br)2(SC6H3-2,5-Me2)(PPh3)2] and [ReO(NNMePh)(SPh)3] and of the synthetic precursor [Re(NNC6H4-4-Br)2Cl(PPh3)2]

    Polyhedron

    (1987)
  • T. Nicholson et al.

    The synthesis and characterization of [MCl3(N:NC5H4NH)(HN:NC5H4N)] from [MO4] (where M=Re, Tc) organodiazenido-organodiazene-chelate complexes. The x-ray structure of [ReCl3(N:NC5H4NH)(HN:NC5H4N)]

    Inorg. Chim. Acta

    (1996)
  • R. Alberto

    Technetium

    CCC II

    (2004)
  • S.S. Jurisson et al.

    Potential technetium small molecule radiopharmaceuticals

    Chem. Rev.

    (1999)
  • S. Liu et al.

    99mTc-labeled small peptides as diagnostics radiopharmaceuticals

    Chem. Rev.

    (1999)
  • S. Liu et al.

    99mTc labeling of highly potent small peptides

    Bioconjug. Chem.

    (1997)
  • J.R. Dilworth et al.

    The biomedical chemistry of technetium and rhenium

    Chem. Soc. Rev.

    (1998)
  • W.C. Eckelman

    Radiolabeling with technetium-99m to study high-capacity and low-capacity biochemical systems

    Eur. J. Nucl. Med.

    (1995)
  • K. Schwochau

    Technetium radiopharmaceuticals: fundamentals, synthesis, structure and development

    Angew. Chem. Int. Ed. Engl.

    (1994)
  • S. Jurisson et al.

    Coordination compounds in nuclear medicine

    Chem. Rev.

    (1993)
  • J. Steigman et al.

    The chemistry of technetium in medicine

    (1992)
  • T.C. Pinkerton et al.

    Bioinorganic activity of technetium radiopharmaceuticals

    J. Chem. Educ.

    (1985)
  • E. Deutsch et al.

    Technetium chemistry and technetium radiopharmaceuticals

    Prog. Inorg. Chem.

    (1983)
  • Int. J. Appl. Radiat. Isot.

    (1983)
  • E. Deutsch et al.

    Heart imaging with cationic complexes of technetium

    Science

    (1981)
  • E. Deutsch et al.

    Recent advances in technetium chemistry: bridging inorganic chemistry and nuclear medicine

    Comment. Inorg. Chem.

    (1984)
  • M.J. Clark et al.

    Medical diagnostic imaging with complexes of 99mTc

    Coord. Chem. Rev.

    (1987)
  • S. Liu et al.

    Technetium complexes of a hydrazinonicotinamide-conjugated cyclic peptide and 2-hydrazinonicotinamide-conjugated cyclic peptide and 2-hydrazinopyridine: synthesis and characterization

    Inorg. Chem.

    (1999)
  • R.M. Pearlstein et al.

    Synthesis and characterization of technetium(V) complexes with amine, alcoholate, and chloride ligands

    Inorg. Chem.

    (1988)
  • T. Konno et al.

    Thiolato-technetium complexes. 2: Synthesis, characterization, electrochemistry, and spectroelectrochemistry of the technetium(III) complexes trans-[Tc(SR)2(DMPE)]+, where R is an alkyl or benzyl group and DMPE is 1,2-bis(dimethylphosphino)ethane

    Inorg. Chem.

    (1989)
  • T. Konno et al.

    Thiolato-technetium complexes. 3: Synthesis and x-ray structural studies on the geometrical isomers cis- and trans-bis(p-chlorobenzenethiolato)bis(1,2-bis(dimethylphosphino)ethane)technetium(III)

    Inorg. Chem.

    (1989)
  • E. Prats et al.

    Mammography and 99mTc-MIBI scintimammography in suspected breast cancer

    J. Nucl. Med.

    (1999)
  • J.P. Leonard et al.

    Technetium-99m-d, 1-HM-PAO: a new radiopharmaceutical for imaging regional brain perfusion using SPECT — a comparison with iodine-123 HIPDM

    J. Nucl. Med.

    (1986)
  • A. Hoepping et al.

    Synthesis and biological evaluation of two novel DAT-binding technetium complexes containing a piperidine based analogue of cocaine

    Bioorg. Med. Chem. Lett.

    (1999)
  • P.D. Acton et al.

    Simplified quantification of dopamine transporters in humans using [99mTc]TRODAT-1 and single-photon emission tomography

    Eur. J. Nucl. Med.

    (2000)
  • P.D. Mozley et al.

    Binding of [99mTc]TRODAT-1 to dopamine transporters in patients with Parkinson's disease and in healthy volunteers

    J. Nucl. Med.

    (2000)
  • S.H.J. Dresel et al.

    In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates

    Eur. J. Nucl. Med.

    (1999)
  • S.K. Megalla et al.

    Specificity of diastereomers of [99mTc]TRODAT-1 as dopamine transporter imaging agents

    J. Med. Chem.

    (1998)
  • H.F. Kung et al.

    Imaging of dopamine transporters in humans with technetium-99m TRODAT-1

    Eur. J. Nucl. Med.

    (1996)
  • D.L. Kukis et al.

    Selectivity of antibody–chelate conjugates for binding copper in the presence of competing metals

    Inorg. Chem.

    (1993)
  • E. Volkert et al.

    Bone-seeking radiopharmaceuticals in cancer therapy

    Adv. Met. Med.

    (1993)
  • R.C. Walovitch et al.

    Characterization of technetium-99m-L, L-ECD for brain perfusion imaging. Part 1: Pharmacology of technetium-99m ECD in nonhuman primates

    J. Nucl. Med.

    (1989)
  • U. Scheffel et al.

    Comparison of technetium-99m aminoalkyl diaminodithiol (DADT) analogs as potential brain blood flow imaging agents

    J. Nucl. Med.

    (1988)
  • K. Itoh

    99mTc-MAG3: review of pharmacokinetics, clinical application to renal diseases and quantification of renal function

    Ann. Nucl. Med.

    (2001)
  • S. Liu et al.

    Fundamentals of receptor-based diagnostic metalloradio-pharmaceuticals

    Top. Curr. Chem.

    (2002)
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