Radionuclide precursors and radiopharmaceuticals for targeted radionuclide imaging and therapy in nuclear medicine

To promote the development and production of modern diagnostic and therapeutic radionuclides and radioimmunopharmaceuticals in new member and associated eu countries.

Targeted radionuclide therapy using particle emitters (alpha, beta and Auger electron emitters) attached to 'smart' biomolecules enter their age of commercial use in nuclear medicine. A good example: the first world approved (FDA) radio-immunotherapeutics (RIT) ZEVALIN (February 2002, IDEC Pharmaceuticals) for therapy of non-Hodgkin's B-cell Lymphoma. The targeting monoclonal antibody (Mab) Rituximab (anti-CD20) is 'equipped' with pure hard beta-emitter Y-90 here. The proposed project aims to develop technologies for production of other therapeutic radionuclides, e.g. reactor produced radionuclides Lutetium-177 (Yb-176;n,gamma;Yb-177 with reaction with subsequent beta-decay of Yb-177 to Lu-177 and the radiochemical separation of 'carrier-free' Lu-177) or Scandium-47 (Ca-46;n,gamma;Ca-47 - beta decay to Sc-47) or accelerator produced Auger-emitter Erbium-165 (Ho-165;p,n;Er-165) using chromatography for separation and purification of Er-165 from the target material. Among alpha-emitters, the production technology of Terbium-149 via cyclotron reaction Gd-152;p,4n;Tb-149 is to be investigated. Other radionuclides to be produced would be positron-emitters Yttrium-86 and Gallium-66 (via cyclotron reactions Sr-86;p,n;Y-86 and Zn-66;p,n;Ga-66) for PET bio-distribution and dosimetry assays of radiolanthanoid therapeutics. Another radionuclide for PET imaging, Gallium-68, will be produced using a Ge-68/Ga-68 generator. This project is aimed mainly at the development of RITs for the treatment of various kinds of cancer disease. DOTA bi-functional macro-cyclic chelates are not suitable for labelling all biomolecules because of slow complication kinetics of radiolanthanoids. Therefore, new DOTA derivatives (e.g. some phosphonic/inic derivatives) for faster and easier synthesis of labelled bio-conjugates at lower temperature will be studied. The selection of perspective Mabs labelled with Y-90 includes, e.g., anti-CEA or 17-1A/EGP2 against colorectal carcinoma or anti-HER2/neu against breast carcinoma. The short-range radionuclides beta (Lu-177), alpha (Tb-149) and Auger electron emitting (Er-165) with tissue-range from about 1 mm to cell cluster, single cell or even single molecule size, are to be studied for labelling of biomolecules (Mabs or peptides) rather than against haematologic malignancies. Examples of such studies are given below: - labelling of the monoclonal antibody conjugate anti-CD66 of granulocytes and their precursors with Lu-177 or Tb-149 for bone marrow ablation, - labelling of the J591 Mab specific for the prostate-specific membrane antigen with Lu-177 for the treatment of prostate cancer, - labelling of the anti-CD74(LL1) Mab with Er-165 (Auger-emitter) for the treatment of B-Cell Lymphoma, - labelling study of bio-conjugates of bombesin analogues with Y-90 and Lu-177. Labelled bombesin analogues are targeted against GRP-R (gastrin-releasing peptide receptors), which are specifically over-expressed on a variety of human tumours like prostate, lung, breast and pancreas. - a very promising branch of RIT is the labelling of anti-VEGF (vascular endothelial growth factor) Mabs and peptides against the neovasculature of proliferating cancer tissue. Preparations of VG76e Mab labelled with Lu-177/172 or As-77/74/72 for imaging and therapy will be synthesised and tested within this project. Development of analytical methods for determination of radiochemical, chemical and radio-nuclide purity of no-carrier-added (carrier-free) labelling radionuclide precursors with very high specific radioactivity will be a very important part of the project. Standard analytical methods like chromatography (HPLC, ITLC, etc.), polarography or ICP-MS will be applied to quality control, but new routine spectrometric methods (e.g. liquid scintillation or thin layer spectrometry) are to be developed for determination of radioactivity and radionuclide purity of very soft Auger emitters. The standard method for determination of general labelling efficiency of radionuclide precursors is to be developed too. For radioactively labelled compounds aimed at potential radiopharmaceuticals, pharmacokinetic and bio-distribution studies in laboratory animals will be performed. The selected animal models of cancer diseases will be tested in in-vitro and in-vivo assays of radio-labelled bio-conjugates.
Project ID: 
3 832
Start date: 
Project Duration: 
Project costs: 
1 330 000.00€
Technological Area: 
Pharmaceutical Products / Drugs
Market Area: 
Nuclear imaging

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