POL-RAD-PHARM · Chemical studies for design and production of new radiopharmaceuticals

Final Activity Report Summary - POL-RAD-PHARM (Chemical studies for design and production of new radiopharmaceuticals)

Task 1 '2+1' mixed-ligand tricarbonyltechnetium(I) complexes with bidentate N-methyl-2-pyridinecarboamide (LNO) and especially with N-methyl-2-pyridinethiocarboamide (LNS) [NP12] are quite stable, as found by histidine challenge [NP17] and theoretical (DFT) calculations [NP1]. The monodentate ligand may be a functionalised imidazol which forms a strong Tc-N bond [AC5]. Also possible is direct labelling of peptides, e.g. bombesin, with the [99mTc(CO)3LNS(H2O)]+ complex [AC5]. The monoligand 99mTc(CO)3+chelate with a tridentate (LNSO) derivative of 2-mercaptohistidine is also very stable, but forms two isomers [NP19], undesirable in nuclear medicine. A novel trifunctional ligand, synthesised in Partner 4 laboratory, makes it possible to: (i) firmly coordinate to 99mTc(CO)3+; (ii) internalise tumour cells; and (iii) intercalate to DNA in the cells. Task 2 Very stable '4+1' mixed-ligand complexes of 99mTc(III) and 188Re(III) with monodentate isocyanide ligand functionalised with c(RDGyK) peptide [CB1, AC3] or stabilised bombesin, [NP20] were obtained. Three tetradentate NS3 ligands [NP11, CB1] were modified to make the complexes hydrophilic to a different degree [NP4]. The complexes were also synthesised at milligram scale with stable rhenium to verify their identity. Similar bioconjugates of 99mTc complexes (with lysine-L2) have been synthesised; it can be used for labelling monoclonal antibodies. Other complexes of Re(V) [AJ3] and Re(I) [AJ4] were also synthesised and studied as potential precursors for therapeutic radiopharmaceuticals. Task 3 Two mixed-ligand astatide complexes, Rh(S4diol)At+ and Ir(S4diol)At+ (S4diol = 1,5,9,13-tetratiacyclohexadecane-3,11-diol) [AJ6], have been synthesised, isolated and proved to be very stable and inert in human serum [NP18]. They bind 211At more strongly than all other precursors known, have a good biodistribution, and seem to be good candidates for application in therapeutical radiopharmacy [AJ5]. Novel Sc3+ (PET nuclide 44Sc and therapeutic 47Sc) complexes with tri- i teraazamacrocyclic ligands have been obtained, much more stable than their Y3+ and lanthanide analogs [NP16]. Inversion in lipophilicity of analogous complexes of Sc3+ and Lu3+ with cyclic ligands: octadentate DOTA and hexadentate NOTA was observed and explained. Novel bisphosphonate complexes of 47Sc and 177Lu for bone pain therapy were synthesised [NP14,S3]. Complementing of the 5 mCi 44Ti/44Sc generator in partner's 8 laboratory [Wa35] made it possible to obtain octreotide peptide by direct labelling the DOTATOC conjugate with 44Sc (98 % yield). After purification and sterilisation the radiopharmaceutical can be injected to patients [Wa36]. Studies on complexing 89Zr, potential PET radionuclide, have been commenced using polydentate cyclic and acyclic ligands [Ca32]. Task 4 The results have been included in the description of Tasks 1-3. Task 5 Method for 177Lu separation from neutron irradiated ytterbium target has been elaborated and patented [Pat1]. Two novel radionuclide generators have been elaborated (lab scale): 82Sr/82Rb (PET tracer) [AJ2] and 103Ru/103mRh (Auger electrons emitter) [NP6, S2]. New methods have been elaborated for production of carrier free soft emitters, 47Sc and 105Rh, potential therapeutic radionuclides. Task 6 Studies on the analytical control on the new sol-gel technology of 188W/188Re generator beads were continued. The results will be used for optimising the system [Ca34]. Two methods of analysis of microamounts of impurities (Se) in various materials were compared: neutron activation analysis and ICP-MS [S4]. Modern ICP-MS spectrometer has been installed at ICHTJ. Three ICHTJ fellows were trained in ICP-MS at two Partners laboratories.

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