Schlüsselwörter
(Englisch)
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Multimodality imaging; targeted contrast agents; positron emission tomography; targeted magnetic resonance imaging; multivalency; bombesin; antagonist.
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Forschungsprogramme
(Englisch)
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COST-Action D38 - Meta-based Systems for Molecular Imaging Applications
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Kurzbeschreibung
(Englisch)
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Multimodality imaging using multimeric targeting vectors could couple the advantages of PET (low concentration), MRI (high resolution) and multivalency (increased binding affinity and favorable pharmacokinetics). We propose to develop novel DOTA-based prechelators for the mono, di and tetravalent conjugation with the peptidyl ligands and to explore these multimeric conjugates as multimodality imaging probes. The vectors will be based on regulatory peptides having affinity towards broad spectrum of tumors. Different spacers will be introduced to modify the biological profiles of the multivalent peptide vectors. The peptides with suitable spacer will be subjected to multivalent conjugation with DOTA-derived chelators and labeled with radionuclides like 68Ga for Positron Emission Tomography (PET) and 111In for Single Photon Emission Computerized Tomography (SPECT). For MRI applications, the multivalent DOTA-peptide conjugates will be complexed with Gd3+. Implementation of multimeric targeting vectors might be ideal to improve tumor targeting as multivalency enhances receptor binding affinity, tumor specificity and tumor retention time. Thus, we propose that a detailed as well as comparative in vitro and in vivo studies of the synthesized mon, di and tetravalent targeting vectors could be highly helpful for the development of lead molecule for tumor targeting. In addition, we expect that due to multimeric receptor binding and increased rigidity, these multivalent systems will have longer rotational correlation times and high proton relaxivities providing improved Gd-based contrast agents for MRI. Overall, the main objective is to develop potential imaging probes based on multimeric targeting vectors which could improve tumor targeting capabilities and also can be employed for multimodal imaging such as PET/MRI or SPECT/MRI for the precise and comprehensive tumor imaging.
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Partner und Internationale Organisationen
(Englisch)
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BE, CH, CY, CZ, DE, ES, FI, FR, GR, HU, IT, NL, PL, PT, UK
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Abstract
(Englisch)
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Multimodal tumor imaging using MRI and PET/SPECT provides comprehensive diagnostic information as it combines anatomical information (by MRI) and functional information (by PET or SPECT). Development of DOTA-derived imaging probes is advantageous for multimodal imaging as it ac-commodates many metal ions employed in different imaging modalities including Gd(III) for MRI. However, high relaxivity and enhanced specific up-take at the targeted site is important for the Gd-based MRI contrast agents. The DOTA-based prochelators required for the multivalent vectorization of targeting ligands were synthesized by functionalizing cyclen or DO2A-tert-butyl ester with modified glutamic acid. Multivalent conjugation of bombesin agonist peptides, which specifically target tumors expressing gastrinreleasing peptide (GRP) receptors, yielded the corresponding mono-, di-, and tetravalent bombesin analogues. The conjugates showed excellent chelating properties with Gd(III) (for MRI applications) and also with 111In, 177Lu and 68Ga (for radiopharmaceutical applications). The 111In and 177Lu labeled divalent bombesin conjugates showed rapid internalization and slower externalization rate compared to their corresponding monovalent analogues as studied with prostate tumor cell lines. Biodistribution studies performed with nude mice bearing PC-3 tumor showed that the divalent conjugate has higher tumor uptake compared to monovalent conjugate. The gadolinium complexes of monovalent and divalent bombesin conjugates showed significant relaxivities at 60 MHz ranging from 9.3 to 19.2 mM-1s-1 at 25°C. The values represent the 2 to 4 fold enhancement of relaxivity compared to clinically employed Dotarem® (Gd-DOTA). Further, the relaxivities increased significantly from monovalent to divalent conjugates. This is highly promising as we would expect much higher relaxivities in case of tetravalent conjugates, which are currently under investigation. In conclusion, the work demonstrates the development of high relaxivity multivalent bombesin analogues, which could be employed for the multimodal imaging such as PET/MRI or SPECT/MRI with improved tumor targeting capabilities. The study also involved the development of a new DOTA-based prochelator for the hybrid vectorization of targeting ligands for bi-specific receptor targeting. In addition, a potent bombesin antagonist was conjugated to four different bifunctional chelators such as DOTA, N4 tetraamine, NODAGA and CB-TE2A and labeled with 111In, 99mTc, 68Ga and 64Cu, respectively. This study revealed that the conjugation of different chelators does influence the affinity and pharmacokinetics of bombesin antagonists significantly. However, the high and selective in vivo tumor uptake assures potential application of these probes for SPECT (111In & 99mTc) and PET (68Ga & 64Cu) imaging.
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Datenbankreferenzen
(Englisch)
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C07.0039
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