5) Metals in Medicine (1) Trace elements, dietary supplements Enzyme inhibitors Fe, Cu, Se, Ca, Mg, Zn Inorganic Pharmaceuticals Therapeutics Diagnostics Anticancer Drugs Radiopharmaceuticals Pt, Ru, Au, Ti, Ga I, Bi, Re Tc, I, Cr, Ga, In, Cu Antiarthritis Drugs Au Antiulcus Drugs X-ray contrast agents Bi Ba, Gd, Dy, I Specific Drugs Fe – High blood pressure MRT contrast agents 3+ 2+ Ag/Sb – Anti infection Rare earths, Fe , Mn 5) Metals in Medicine (2) Anticancer Drugs Cis-platin Cl N H Pt 3 Cl N H 3 Mechanism of Activity • Primarily by interaction with DNA in the nuclei of the cells 2+ • Coordination of {(NH3)2Pt} fragments to guanidine units • Deformation of DNA 1 5) Metals in Medicine (3) Anticancer Drugs Cis-platin Problems • Low solubility • Complex distribution chemistry, • Hydrolysis in stomach, only i.v. applicable • Unfavourable side-effects Hydrolysis and species cis-[PtC l2(N H 3)2] + C l- - C l- langsam slow + H + cis-[PtC l(N H ) (O H )] + 3 2 cis-[PtC l(N H 3)2(H2O )] - H + + C l- - C l- schnell fast + H + + H + + cis-[Pt(N H ) (H O) ]2+ cis-[Pt(N H 3)2(O H )2] cis-[Pt(N H 3)2(O H )(H 2O )] 3 2 2 2 - H + - H + pKs = 7,3 pKs = 5.6 oligomersO ligom ere 5) Metals in Medicine (4) Anticancer Drugs Cis-platin Cl N H Pt 3 Cl N H 3 Distribution in the body Injection Undesired side-effects Blood Anti-cancer activity Binding to plasma proteins Transport by the bloodstream Kidney Other organs Tumor Excretion Liver 2 5) Metals in Medicine (5) Anticancer Drugs Cis-platin derivatives Second generation of cis-platin derivatives • Lower dose • Better solubility • Less side-effects 5) Metals in Medicine (6) Anticancer Drugs Cis-platin derivatives Other platinum drugs under research Pyriplatin • Violates the ‚classical‘ structure-activity rules • Forms monodentate DNA adducts 3 5) Metals in Medicine (7) Anticancer Drugs Cis-platin derivatives Novel drug delivery strategies for platinum drugs 5) Metals in Medicine (8) Anticancer Drugs Ruthenium complexes 4 5) Metals in Medicine (9) Anticancer Drugs Anticancer Drugs Titanium complexes Gold complexes O N Cl N O C C H3 Au Au Cl O C C H3 O Ph Ph + P P Ph Ph Au Ph Ph P P Ph Ph 5) Metals in Medicine (10) Antiarthritis Drugs Gold complexes Polymeric compounds with thiolato ligands Au S Na O O Na C H H O 2 O HC O H O S O H O S Au Au H C H O O H 2 n S O 3 Na thiomalic acid thioglucose thiopropanolsulfonate Only structurally established compound: Complex with thiomalic acid 5 5) Metals in Medicine (11) Antiarthritis Drugs Gold complexes Molecular compounds Auranofin, an orally applicable drug OAc Et O OAc S Au P Et OAc OAc Et • Mechanism of activity hitherto unclear • Intracellular ligand exchange probable • Sulphur-containing biological compounds (gluthatione, cysteine, methionine - • Well-known metabolite: [Au(CN)2] 5) Metals in Medicine (12) AntiarthritisAntiulcus Drugs Drugs Basic bismuth nitrate, salicylate or citrate GoldBi complexes For treatment of inflammations of the gastroindestinal tract Polymeric structure of Na2[Bi2(citrate)2] • More than 200 years history • Treatment of gastroindestinal tract • pH regulation and desinfection • Mechanism mostly unclear • Compounds: basic Bismuth(III) salts • Hydrolysis in water and formation of hydroxo- bridged frameworks • Formation of polymeric layers covering the Cage of [Bi O (OH) ](NO ) · 6 H O inflamation areas 6 4 4 3 6 2 6 5) Metals in Medicine (13) Specific Drugs Fe – High blood pressure Ag/Sb – Anti infection Desinfection „Classical“ use of toxic metal ions such as Ag+, Sb3+, Sb5+ Silver sulfadiazine Renewed interest by anti-malarial and anti HIV activities of this and related compounds 5) Metals in Medicine (14) Specific Drugs Fe – High blood pressure Ag/Sb – Anti infection Anti-malaria Anti HIV Desferrioxamine Bi-cyclame derivative Siderophore: Influences the Fe metabolism of Influences replication cycle of HIV the malaria parasite virus Insuline mimetics • Simple Vanadium(V) or –(IV) compounds • Relatively less dependent on structure • Use of less toxic complexes with organic V(IV) maltolato complex ligands 7 5) Metals in Medicine (15) X-ray contrast agents Ba, Gd, Dy, I, W • Agents with heavy atoms (Barium, Iodine, other heavy metals) • „Classical use“: BaSO4 for X-ray studies of gastroindestinal tract • For blood vessels: iodinated compounds, heavy metals in research Iodinated compounds: e.g. Example: rat leg „Normal“ X-ray Iodohexol Na6[P2W18O62] 5) Metals in Medicine (16) MRT contrast agents Rare earths, Fe3+, Mn2+ NMR tomography • Measurements of proton signals (H2O) in different environments • Important parameter: relaxation behaviour of the protons (T1 and T2) • Influence of paramagnetic compounds on T1 (shortening) • With this, increase of the „contrast“ of the images Paramagnetic compounds in use: • Rare earth (mostly Gd3+) complexes with a H2O ligand • Mn2+ complexes • Superparamagnetic iron oxide nanoparticles in organic (dextrane) layer 8 5) Metals in Medicine (17) MRT contrast agents Rare earths, Fe3+, Mn2+ 5) Metals in Medicine (18) MRT contrast agents Rare earths, Fe3+, Mn2+ Research Strategies 9 5) Metals in Medicine (19) Radiopharmaceuticals I, Bi, Re Tc, I, Cr, Ga, In, Cu Therapy Diagnostics destruction of (cancer) cells Imaging of organs - short range - medium range - high dose - low dose - strongly ionising radiation - - emitter - - - emitter - + - emitter - - emitter 5) Metals in Medicine (20) Radiopharmaceuticals I, Bi, Re Tc, I, Cr, Ga, In, Cu Nuclearmedical Therapy, Targeting - - emitter Isotope t (d) Energy (E MeV) 1/2 max, 32P 14,3 1,71 - short range 47Sc 3,4 0,6 64Cu 0,5 0,57 - high dose 89Sr 50,5 1,46 - strongly ionisating radiation 90Y 2,7 2,27 102Rh 1,5 0,57 - - - emitter 111Ag 7,5 1,05 131I 8,0 0,81 - - emitter 153Sm 1,9 0,8 186Re 3,8 1,07 - emitter Problem Isotope t (d) Energy (E MeV) 1/2 max, Partially high radiations dose to 211At 7,2 h 6,8 the rest of the organism 212Bi 1,0 h 7,8 10 5) Metals in Medicine (21) Radiopharmaceuticals I, Bi, Re Tc, I, Cr, Ga, In, Cu Nuclearmedical Diagnostics + - Emitter - Medium range Isotope t1/2 - Energy (MeV) - Low dose 11C 20,4 min 0,5 13N 9,9 min 0,5 - - emitter 15O 2,0 min 0,5 18 - + - emitter F 110,0 min 0,5 - Emitter PET (Positron Emission Tomography) Isotope t1/2 - Energy (MeV) 131I 8,0 d 0,36 99mTc 6,0 h 0,14 SPECT (Single Photon Emission Computer Tomography) 5) Metals in Medicine (22) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics Emission of a positron (ß+-particle) Annihilation of a positron • a positron is not stable and reacts immediately with an electron under formation of two -quants • transformation of matter into energy • no ß+-spectra are measured • instead of this, two -quants with distinct energy ( ≈ 500 keV) can be detected (E = m c2) • the angle between the quants is exactly 180° 14F 15F 16F 17F 18F 19F 20F 21F 22F 23F 24F 25F 26F 27F 28F 29F 30F 31F proton, EC, positron (ß+) ß- 11 5) Metals in Medicine (23) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics Nuclear reaction: 18O (p,n) 18F Cyclotron Target: 18O-enriched water Proton energy: 15 - 16 MeV Irradiation time: 2 h 14F 15F 16F 17F 18F 19F 20F 21F 22F 23F 24F 25F 26F 27F 28F 29F 30F 31F proton, EC, positron (ß+) ß- 5) Metals in Medicine (24) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics 18F Fluorodesoxyglucose 18F DOPA Glucose metabolism Neurotransmitter, receptors 18F Methyltyrosin 18F Fluorothymidin 18F 5-Fluorouracil Metabolism of amino acids DNA/RNA synthesis Therapy, pharmacokinetics 14F 15F 16F 17F 18F 19F 20F 21F 22F 23F 24F 25F 26F 27F 28F 29F 30F 31F proton, EC, positron (ß+) ß- 12 5) Metals in Medicine (25) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics Automated synthesis modul Product 18F FDG in isotonic saline / citrate buffer Reaction scale: up to 10.000 GBq 14F 15F 16F 17F 18F 19F 20F 21F 22F 23F 24F 25F 26F 27F 28F 29F 30F 31F proton, EC, positron (ß+) ß- 5) Metals in Medicine (26) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics Classical positron emission tomograph 14F 15F 16F 17F 18F 19F 20F 21F 22F 23F 24F 25F 26F 27F 28F 29F 30F 31F proton, EC, positron (ß+) ß- 13 5) Metals in Medicine (27) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics Slice images brain myocardium tumor 5) Metals in Medicine (28) Radiopharmaceuticals PET I, Bi, Re Tc, I, Cr, Ga, In, Positron emisson tomography Cu Nuclearmedical Diagnostics Three dimensional reconstitution 14 5) Metals in Medicine (29) Radiopharmaceuticals SPECT I, Bi, Re Tc, I, Cr, Ga, In, Single Photon emisson computer tomography Cu Nuclearmedical Diagnostics SPECT with 99mTc 5) Metals in Medicine (30) Radiopharmaceuticals SPECT I, Bi, Re Tc, I, Cr, Ga, In, Single Photon emisson computer tomography Cu Nuclearmedical Diagnostics 99mTc - as a „metastable“ nuclear isomer 99Mo 86 % 66h 14 % 99mTc 99mTc 99 99 Tc 6h Tc 5 2,13 10 a 99Ru (stabil) 15 5) Metals in Medicine (31) Radiopharmaceuticals SPECT I, Bi, Re Tc, I, Cr, Ga, In, Single Photon emisson computer tomography Cu Nuclearmedical Diagnostics 99Mo/99mTc nuclide generator Concentration of the 99mTc in the eluate of the generator: about 10-9 mol/l - Chemical form: pertechnetate, TcO4 5) Metals in Medicine (32) Radiopharmaceuticals SPECT I, Bi, Re Tc, I, Cr, Ga, In, Single Photon emisson