Synthesis of biomolecules for nuclide therapy : Studies on amino acids, nucleosides and isoquinolines

Sammanfattning: Nuclide therapy for cancer is based on the selective delivery of nuclide bearing compounds to tumour cells. Radionuclides, such as 125I, may be used, as well as stable isotopes, such as 10B, which is activated on site by an external neutron source. The second methodology is used in Boron Neutron Capture Therapy, which utilises the cytotoxic effect from the neutron capture reaction 10B(n,α)7Li. With this background in mind, nuclide bearing amino acids, nucleosides, and isoquinolines have been synthesised.Carborane containing analogues of phenylalanine were asymmetrically synthesised using Oppolzer's camphor-derived chiral handle. The (R)- and (S)-[3-(1,7-dicarba-closo-dodecaborane(12)-1-yl)-2-aminopropanoic acid] (meta-carboranylalanine), were obtained in >99 % enantiomeric purity. The (S)-Boc-ortho-carboranylalanine was obtained in two steps from (2S,2'S)-N-(3'(1",2"-dicarba-closo-dodecaborane(12)-1"-yl)-2'-aminopropanoyl)bornane-10,2-sultam.Three carborane containing thymidine derivatives 3'-O-(o-carboran-1-ylmethyl)thymidine, 7-(thymidine-3'-ylmethyl)dodecahydro-7,8-dicarba-nino-undecaborate, and 3'-O-(p-carboran-1-ylpropyl)thymidine were synthesised from thymidine. In vitro evaluation regarding enzymatic phosphorylation is described.Three iodo-analogues of the peripheral benzodiazepine receptor (PBR) ligand PK 11195, namely the isoquinoline derivatives N-Methyl-N-(1-methylpropyl)-1-(2-iodo phenyl)isoquinoline-3-carboxamide, N-Methyl-N-(1-methylpropyl)-1-(3-iodophenyl) isoquinoline-3-carboxamide, and N-Methyl-N-(1-methylpropyl)-1-(4-iodophenyl)isoquinoline -3-carboxamide were synthesised and radiolabelled with 125I.The carborane containing isoquinoline derivative N-Methyl-N-(1-methylpropyl)-l-[2'-(l"-7"-dicarba-closo-dodecaborane(12)-l"-yl)ethyl]isoquinoline-3-carboxamide was synthesised as a potential PBR-ligand.