Metallocarborane-based bisphosphonates for tumour imaging and therapy

Abstracts / Nuclear Medicine and Biology 37 (2010) 677–726

Acknowledgment M. Batista thanks FCT for the postdoctoral grant (SFRH/BPD/46842/2008).

References [1] Wängler C, Schirrmacher R, Bartenstein P, Wängler B. Bioorg Med Chem Lett 2009;19:1926. [2] Liu S. Adv Drug Deliv Rev 2008;60:1347. [3] Lacerda S, Campello MP, Marques F, Gane L, Kubíček V, Fousková P, et al. Dalt Trans 2009:4509.

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tridentate ligand and trans to a chloride. The phosphine components of the PNP ligand adopt a mutually trans orientation. Analogous reactions in methanol, however, require reflux to dissolve the lipophilic PNP ligand and generates the Tc(I) fac-[TcCl2(NO)(PNPpr)] isomer as the major product. In this complex the tridentate PNP ligand is coordinated in a facial arrangement with the tertiary amine trans to the nitrosyl (νNO=1789 cm-1). The chlorides and nitrosyl occupy the remaining three sites. The choice of solvent and reaction conditions employed play a critical role in determining which of the two coordination isomers is predominant in these redox substitution reactions. doi:10.1016/j.nucmedbio.2010.04.154

doi:10.1016/j.nucmedbio.2010.04.162 Multimeric cyclam derivatives with tunable surface modification for radiopharmaceutical applications Manja Kuhlman a, Holger Stephan a, Jörg Steinbach a, Anika Röhrich b a Forschungszentrum Dresden-Rossendorf, 01314 Dresden, Germany b B CUBE Technische Universität Dresden, 01307 Dresden, Germany Due to the emerging possibilities of metabolic stabilization as well as to induce multivalency effects in receptor-ligand interaction, multimeric amino acid derivatives gain specific interest. An intriguing approach is the development of cluster compounds which possess both superficial peptide units and centralarranged chelating agents. In doing so, dendritic encapsulated radiometal complexes with tunable solubility and targeting properties become available which can be utilized for diagnostic and therapeutic purposes. The decay profile of copper radioisotopes, such as 64Cu and 67Cu, offers such possibilities. Azamacrocycles are appropriate building blocks to form very stable complexes with copper(II) and their carboxylate-containing analogues permit the coupling of biomolecules. In this context, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid is quite often used for copper-based radiopharmaceutical featuring. Surprisingly, radiolabeling of the corresponding propionic acid derivative — 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid — has not been reported so far. Cyclam derivatives with one to four appending propionic acid groups were synthesized. After surface modification with the dipeptide Arg-Tyr as well as the specific hexapeptide neurotensin(8-13), kinetics of complex formation with copper(II) were investigated by ultraviolet-visible spectroscopy. Radiolabeling experiments with 64Cu on selected compounds showed fast and efficient complexation. doi:10.1016/j.nucmedbio.2010.04.066

Technetium-labelled cathepsin B inhibitors as molecular imaging agents Patricia E. Edem a, John F. Valliant a,b a Department of Chemistry, McMaster University, W. Hamilton, ON L8S 4K1 b Department of Medical Physics and Applied Radiation Sciences, McMaster University, W. Hamilton, ON L8S 4K1 Cathepsin B is cysteine protease that is overexpressed in highly aggressive breast cancer cells. Dipeptidyl (acyloxy)methyl ketones are a class of compounds that have shown selective and effective inhibition of cathepsin B. The 99mTc derivative of the lead compound Z-Phe-Lys-CH2OCOPhMe3, which has a Ki=170±50 nM, could therefore act as a molecular imaging agent capable of targeting cathepsin B and by design aggressive breast cancer tumours. The presentation will describe the synthesis of the ligand, the coordination chemistry with rhenium and the radiochemistry with Tc(I). The screening data on the rhenium derivative based on a colorimetric plate assay to determine the binding affinity to cathepsin B in vitro will be presented and compared to existing lead agents. doi:10.1016/j.nucmedbio.2010.04.164 Metallocarborane-based bisphosphonates for tumour imaging and therapy Michael Cooke a, John F. Valliant a,b a Department of Chemistry, McMaster University, W. Hamilton, ON L8S 4K1 b Department of Medical Physics and Applied Radiation Sciences, McMaster University, W. Hamilton, ON L8S 4K1 There remains a need for radiopharmaceuticals that can deliver large payloads of therapeutic radionuclides to tumours that have metastasized to

Poster Communications The synthesis and structural characterization of new Tc(I) nitrosyl complexes Terrence Nicholson a, Ashfaq Mahmood a, Fiorenzo Refosco b, Frencesco Tisato b, Peter Müller c, A.G. Jones a a Department of Radiology, Harvard Medical School, Boston, MA 02115, USA b ICIS-CNR, 35100 Padova, Italy c Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA The stable 99Tc(II) nitrosyl complex (Bu4N)[TcNOCl4] reacts with the tridentate ligand bis[(2-diphenylphosphino)propyl]amine (PNPpr) to form 99 Tc(I) [TcCl2(NO)(PNPpr)] complexes with mer or fac geometries, both of which have been structurally characterized by X-ray crystallography. The PNPpr, ligand which is freely soluble in MeCN, reacts at room temperature to yield mostly the mer-[TcCl2(NO)(PNPpr)] isomer, which displays the nitrosyl (νNO=1689 cm−1) cis to the tertiary amine of the

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Fig. 1.

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Abstracts / Nuclear Medicine and Biology 37 (2010) 677–726

bone and that do not degrade prematurely in solution or in vivo at high activity concentrations. To address this challenge, a compartmentalized approach to radioimaging and therapy of bone metastases was developed by employing the 1-hydroxy-1,1-bisphosphonate targeting vector linked to a carborane ligand which forms robust Re and Tc complexes. The synthesis and characterization of the novel ligand and Re(I) complexes and biological evaluation of their corresponding 99mTc(I) analogues in vivo will be presented. These data will be compared to the corresponding iododerivatives highlighting the versatility of carboranes which is one of only a limited number of ligands that can bind to both radiometals and radiohalogens (Fig. 1). doi:10.1016/j.nucmedbio.2010.04.170 bis-Benzimidazole single-amino acid chelates a

a

introduction of a variety of substituents to modify the reactivity and log P of the ligand. The parent compound (SAACB) was prepared in large quantities and labeled quantitatively with 99mTc(CO)3 at room temperature and isolated in 68% yield. A biodistribution study of [SAACB-99mTc(CO)3]+ was performed in balb/c female mice and showed decreased liver uptake relative to the more hydrophilic quinoline analogue. Details on the radiochemistry, biodistribution and characterization of the ligand including a crystal structure of [SAACB-Re(CO)3]+ will be presented. doi:10.1016/j.nucmedbio.2010.04.182 Bioconjugated Re and Tc-99 carbonyls by transmetallation with Zn(II) compounds Joan Lecina a, Alessia Carrer b, Angel Álvarez-Larena c, Ulderico Mazzi b, Joan Suades a a Department of Chemistry, Universitat Autònoma de Barcelona, Spain b Department of Pharmaceutical Sciences, University of Padova, Italy c X-ray Diffraction Service, Universitat Autònoma de Barcelona, Spain

a,b

Alla Darwish , Michael Cooke , John F. Valliant a Department of Chemistry, McMaster University, Hamilton, Ontario, Canada L8S 4M1 b Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario, Canada L8S 4M1

The aim of this work is to develop an innovative method to prepare technetium and rhenium compounds using a transmetallation reaction. The Zn(II) dithiocarbamate of isonipecotic acid was chosen because of its high stability, low toxicity and by the accessibility to bioconjugation reactions through the carboxylic group. The succinimidyl ester of this compound (1, see the Scheme 1) was prepared by a convenient method in high yield and isolated as a stable solid. It reacts cleanly with primary and secondary amines to yield the respective compounds 2–5 which can also be isolated. The transmetallation reaction between 2–5 and a rhenium precursor led to complexes 6–9. This reaction is so favourable that takes place in water at very low metal concentrations (≈10 ppm) although 2–5 show very low solubilities in this medium. Consequently, this approach can led to labelled compounds with a very high ratio: labelled biomolecule/non-labelled biomolecule. doi:10.1016/j.nucmedbio.2010.04.070 Synthesis, radiolabeling and evalution of misonidazole analogue to target tumor hypoxia A series of new hydrophilic ligands were developed as synthons for the preparation of isostructural pairs of luminescent and radioactive Re(I) and Tc(I) complexes. The bis-benzimidazole M(I) ligand, SAACB, was synthesized from commercially available starting materials in high yield (75%). The methodology was sufficiently versatile to enable the

99m

Tc(CO) 3 -labeled

Madhava B. Mallia a, Anupam Mathur a, Sharmila Banerjee b, H.D. Sarma a, Meera Venkatesh a a Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai – 400085, India b Radiation Biology and Health Science Division, Bhabha Atomic Research Centre, Mumbai – 400085, India

Scheme 1.