Book of Abstracts - Ruhr-Universität Bochum

OP-36
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Syntheses of New Isomeric Analogues of HYNIC for Evaluation
as a Bifunctional Chelator for Technetium-99m
Anica Dose, a L. K. Meszaros, b S. C. G. Biagini* a and P. J. Blower* b
a University of Kent, Functional Materials Group, School of Physical Sciences, Canterbury CT2 7NH,
UK. b Kings College London, Division of Imaging Sciences, Rayne Institute 4 th Floor Lambeth Wing,
St. Thomas’ Hospital, London SE1 7EH, UK. E-mail: ad308@kent.ac.uk
N
N
Tc
N
N
N
N Tc
1 2
Fig 1: possible monodentate 1
and chelating 2 structures of Tc-
HYNIC complex
Introduction: Technetium, as a meta-stable isotope is extensively used in
nuclear medicine. It is a transition metal of the 7 th subgroup with all formal
oxidation states between -1 and +7 accessible and therefore possesses a large
range of coordination structures. 1 Since the first use of radiolabelled
antibodies with the bifunctional chelator 6-hydrazinonicotinamide (6-HYNIC)
3, 2 the use of radiopeptides with the metastable isotope of technetium 99m Tc as
an imaging agent for cancer cells has increased significantly until today. 3
However, robust structural data for these conjugates is lacking. The HYNIC
and 99m Tc coordinating sphere is still not fully determined and previous studies provide ambiguous
results about the complex. 4 To radiolabel a peptide with HYNIC and 99m Tc also requires one or more
co-ligands to fulfil the coordination sphere around the metal. Different co-ligands can have different
effects on the homogeneity and stability of the complex and its biodistribution. Finally they are
responsible for the formation of more than one end product. The latest results gives a clear insight that
there is one chelating HYNIC per metal site and the oxidation state of Tc is formally +5. 5 The question
as to which mode of the HYNIC coordination, monodentate 1 or chelating 2 is operating, remains
uncertain.
Aims: The aim of this project is to assess the specific binding of the complex between HYNIC and Tc,
Tc and co-ligands and a further investigation of potential direct interactions between Tc and the
peptide. 6
Results: Isomeric HYNIC analogues
4-7 were synthesised. These syntheses
are related to the synthesis of 6-
HYNIC-Boc. 2 The preparation of
HYNIC-rhenium crystals, will provide
new data about the binding structure
and this will be followed by the
preparation of analogous HYNIC-Tc
HO O
N
HO O
crystals. The novel synthesis of Fmoc-Lysine-NHS-2-HYNIC-Boc was also succesfully accomplished.
This will allow for its use in solid phase peptide synthesis (SPPS) to synthesise the “nanogastrin”
peptide [Lys(R)-Glu-Ala-Tyr-Gly-Trp-Met-Asp-PheNH2] where R= HYNIC, which binds to the
CCK-2 receptor overexpressed on certain tumours. 7
Further work will evaluate the new ligands for labelling with Tc-99m and investigate the structural
chemistry of the rhenium and technetium-99m complexes.
References
1. U. Abram, R. Alberto, J. Braz. Chem. Soc. 2006, 17, 1486-1500.
2. M. J. Abrams, M. Juweid, C. I. Tenkate, D. A. Schwartz, M. M. Hauser, F. E. Gaul, A. J. Fuccello,
R. H. Rubin, H. W. Strauss, A. J. Fischman, J. Nucl. Med. 1990, 31, 2022-2028.
3. M. L. Bowen, C. Orvig, Chem. Commun. 2008, 41, 5077-5091.
4. L. K. Meszaros, A. Dose, S. C. G. Biagini, P. J. Blower, Inorg. Chim. Acta 2010,
DOI:10.1016/j.ica.2010.01.009
5. R. C. King, M. Surfraz, S. Biagini, P. J. Blower, S. J. Mather, Dalton Trans. 2007, 43, 4998-5007.
6. M. Surfraz, R. King, S. J. Mather, S. Biagini, P. J. Blower, J. Inorg. Biochem. 2009, 107, 971-977.
7. R. King, M. B. U. Surfraz, C. Finucane, S. C. G. Biagini, P. J. Blower, J. Nuc. Med. 2009, 50, 591-
598.
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N
H
N
NH 2·HCl
HCl·H 2N
H
N
HO O
HO O
HO O
HN
HN
N
HN
NH2·HCl NH2 3 4 5 6 7
Fig 2: HYNIC analogues
N
Cl
N
H
N
NH 2·HCl
NH 2·HCl