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Ligandy pro aplikaci v medicíně H 5 dtpa H 4 dota H 3 do3 a H 4 teta.

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Prezentace na téma: "Ligandy pro aplikaci v medicíně H 5 dtpa H 4 dota H 3 do3 a H 4 teta."— Transkript prezentace:

1 Ligandy pro aplikaci v medicíně H 5 dtpa H 4 dota H 3 do3 a H 4 teta

2 Kontrastní látky pro NMR diagnostiku BEZ kontrastní látky s extracelulárním Gd(III) s angiografickým Gd(III)

3 Metal – ligand bond Coordination compounds Magnetic Resonance Imaging MRI Complexation of Radinuclides milions MR examinations in US ( 25 % ) In world near 100 milions examinations Contrast agents are used for more than 35 % Examinations

4 Principles of NMR and MRI NMR NMR – variable frequency – positions of peaks

5 MRI – intensity of peak (water protons) + spatial resolution – field gradient Principles of MRI The figure was adopted from U. S. patent ‘832 of Dr. R. Damadian on 3D MRI scanner. The patent was filled on March 17, P. C. Lauterbur, P. Mansfield ( Nobel Prize 2003 ), R. Ernst (1991) Discrete Fourier Transormation

6 Contrast in MRI originaters from different water concentration among different types of tissue and also from different relaxation rates of water protons Proton longitudinal T 1 magnetic relaxation times Proton transversal T 2 T 1 – positive contrast, T 2 – negative contrast Principles of MRI

7 Contrast agents for MRI diagnostics Contrast agents are used for more than 35 % Contrast agents are used for more than 35 % examinations 95 % CAs are based on Gd(III) 95 % CAs are based on Gd ( III ) – Proton longitudinal T 1 – paramagnetic species – Proton transversal T 2 – ferromagnetic species

8 Interakce molekul vody s komplexem gadolinia (III) relaxivity r 1 Účinnost kontrastní látky se vyjadřuje pomocí relaxivity, r 1 r1 = f (  M,  R,  M ss, T 1, 2e ) MMMM  M ss rrrr

9 Teoretický profil relaxivity Teoretický profil relaxivity při 20 MHz, 37 °C  R – log(  R )  M – log(  M ) r1r1r1r1

10 ( 1 H NMRD profile) ( 1 H NMRD profile) T = 37  C, 298  v = 40 ps,  2 = s  2, R GdH = 3.1 Å. Šedá oblast Šedá oblast označuje oblast magnetických polí používaných v klinické praxi. Simulace relaxivity jako funkce protonové Larmorovy frequence

11 Příklady ligandů používaných v MRI H 4 dota Dotarem ®, ProHance ®, Gadovist ® H 5 dtpa Magnevist ®, Omniscan ®, MultiHance ®, OptiMARK ®, Eovist ®, AngioMARK ®

12 Struktura komplexů [Gd (dtpa)] 2– [ Gd (dtpa)] 2– [Gd (dota)] – [ Gd (dota)] –

13 Bifunkční deriváty kyseliny fosfinové s optimální hodnotou  M s optimální hodnotou  M 10 – 40 ns P. Hermann, J. Kotek, V. Kubíček, I. Lukeš : Dalton Trans., 2008, I. Lukeš, J. Kotek, P. Vojtíšek, P. Hermann: Coord. Chem. Review, 2001, 216, P. Vojtíšek, P. Cígler, J. Kotek, J. Rudovský, P. Hermann, I. Lukeš: Inorg. Chem., 2005, 44, J. Kotek, J. Rudovský, P. Hermann, I. Lukeš: Inorg. Chem., 2006, 45, r 1  R r 1 = f ( q,  M,  R,  M SS, T 1, 2 e )

14 H 5 do3aP PrA H 4 do3aP ABn vhodné pro konjugaci MRI kontrastních látek na makromolekulu Bifunkční deriváty kyseliny fosfinové s optimální hodnotou  M Bifunkční deriváty kyseliny fosfinové s optimální hodnotou  M 10 – 40 ns J. Rudovský, J. Kotek, P. Hermann, I. Lukeš, V. Mainero, S. Aime: Org. Biomol. Chem., 2005, 3, 112 M. Polášek, J. Rudovský, P. Hermann, I. Lukeš, L.V. Elst, R. N. Muller: Chem. Comm., 2004, 2602 M. Polášek, M. Šedinová, J. Kotek, L.V. Elst, R. N. Muller, P. Hermann, I. Lukeš: Inorg. Chem., 2009, 48, M. Polášek, J. Kotek, P. Hermann, I. Císařová, K. Binneman, I. Lukeš: Inorg. Chem., 2009, 48,

15 The chemical / physical features that affect  R Slow molecular tumbling Immobilization of low-molecular Gd(III) complexes Immobilization of low-molecular Gd ( III ) complexes Covalent – linear carrier, spheric carrier r 1  R r 1 = f ( q,  M,  R,  M SS, T 1, 2 e )

16 Šplhání na vrchol reálného profilu  M – log(  M )  R – log(  R ) r1r1r1r1 H 6 dt4aP H 5 do3aP H 5 dtpa, H 4 dota H 5 dt4aP ABn konjugát inulinu H 5 do3aP ABn PANAM konjugát H 5 do3aP ABn PANAM konjugát + arginin

17 Synthesis of conjugates… Synthesis of conjugates …

18 1 H NMRD profiles of Gd(III)DO3A-P BnN{CS} conjugate with ß-cyclodextrine 1 H NMRD profiles of Gd ( III ) DO3A-P BnN{CS} conjugate with ß-cyclodextrine

19 Multimodal Probes Dual Probes Labelling of Cells Distribution of the Cells in Organism

20 Dual Probes

21 PAMAM dendrimers conjugates Fluorescent photomicrographs of Langerhans islets labeled by G6.9F0.1Ca) b) c)d) Fluorescent photomicrographs of Langerhans islets labeled by G6.9F0.1C: a) visualization of the contrast agent (green) and karyons (blue); b) highlighting of the a-cells (yellow-orange); c) highlighting of the macrophages (yellow-orange); d) highlighting of the b-cells (pink). Islets were incubated with 1 mm G6.9F0.1C (per Gd III ) for 24 h. A typical size of the LIS is 300 μm. c(c)c(c) d(d)d(d) a(a)a(a) b(b)b(b)

22 MRI

23 Targeting Similar strategy would be applied for development of optical and combined imaging probes. Gd

24 Relaxometric parameters of Gd(III)–DOTAPP and related ligands Relaxometric parameters of Gd ( III ) – DOTAPP and related ligands DOTAPP 0.32   1135   BPAMD a BPAPD b DOTA c Ligand  2 [10 20 s –2 ] 298  v [ps] 298  RH [ps] 298  M [  s] r 1 [s –1 mM –1 ] a V. Kubíček, J. Rudovský, J. Kotek, P. Hermann, L. Vander Elst, R. N. Muller, Z. I. Kolar, H. T. Wolterbeek, J. A, Peters, I. Lukeš: J. Am. Chem. Soc., 2005, 127, – b T. Vitha, V. Kubíček, P. Hermann, L. Vander Elst, R. N. Muller, Z. I. Kolar, H. T. Wolterbeek, W. A. P. Breeman, I. Lukeš, J. A. Peters: J. Med. Chem., 2008, 51, 677 – 683. c D. H. Powell, O. M. N. Dhubhghaill, D. Pubanz, L. Helm, Y. S. Lebedev, W. Schlaepfer, A. E. Merbach: J. Am. Chem. Soc., 1996, 118, 9333 – 9346

25 Biodistribution of 177 Lu-complexes in Lewis rat 24 h after injection Biodistribution Lu-c1 Lu-c3

26 SPECT/CT Imaging of Rats SPECT/CT Imaging of Rats V. Kubíček, J. Rudovský, J. Kotek, P. Hermann, L. Vander Elst, R. N. Muller, Z. I. Kolar, H. T. Wolterbeek, J. A, Peters, I. Lukeš: J. Am. Chem. Soc., 2005, 127, – h p.i. 24 h p.i. 177 Lu-c1 75 – 80 MBq

27 PET 18 F (110) min., 11 C (20 min.) – cyclotron Combination of PET and MRI, PET and CT 68 Ga (60 min.), generator

28 PET/CT imaging of osteoblastic bone metastases with 68 Ga-bisphosponates – First in human study (a)(b)(c) (a) = coronal PET, (b) = sagittal PET/CT. For comparison (c) shows 18 F-fluoride PET. University of Mainz, Zentral Klinik Bad Berka


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