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Ligandy pro aplikaci v medicíně
HO2C
HO2C
CO2H
N
N
N
H5dtpa
HO2C
N
N
CO2H
HO2C
N
N
CO2H
CO2H
CO2H
H4dota
HO2C
N
N
CO2H
HO2C
N
N
CO2H
HO2C
H
H4teta
H3do3
a
N
N
CO2H
N
N
CO2H
Kontrastní látky pro NMR diagnostiku
BEZ kontrastní látky
s extracelulárním
Gd(III)
s angiografickým
Gd(III)
Coordination compounds
Metal – ligand bond
Magnetic Resonance Imaging MRI
Complexation of Radinuclides
2005
23 milions MR examinations in US (25 %)
In world near 100 milions examinations
Contrast agents are used for more than 35 % Examinations
Principles of NMR and MRI
NMR – variable frequency
– positions of peaks
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, 1972.
MRI – intensity of peak (water protons) +
spatial resolution – field gradient
P.C. Lauterbur, P. Mansfield
(Nobel Prize 2003),
R. Ernst (1991)
Discrete Fourier Transormation
Principles of MRI
Contrast in MRI originaters from different water concentration among different
types of tissue and also from different relaxation rates of water protons
Proton longitudinal T1
magnetic relaxation times
Proton transversal T2
T1 – positive contrast, T2 – negative contrast
Contrast agents for MRI diagnostics
Proton longitudinal T1 – paramagnetic species
Proton transversal T2
– ferromagnetic species
Contrast agents are used for more than 35 % examinations
95 % CAs are based on Gd(III)
Interakce molekul vody
s komplexem gadolinia (III)
M
Účinnost kontrastní
látky se vyjadřuje
pomocí relaxivity, r1
Mss
r1 = f(M , R , Mss , T1,2e )
r
Teoretický profil relaxivity při 20 MHz, 37 °C
r1
– log(R)
– log(M)
Simulace relaxivity jako funkce
protonové Larmorovy frequence
(1H NMRD profile) T = 37 C, 298v = 40 ps, 2 = 1019 s2, RGdH = 3.1 Å.
Šedá oblast označuje oblast magnetických polí používaných v klinické praxi.
Příklady ligandů používaných v MRI
HO2C
HO2C
N
N
N
N
CO2H
H4dota
Dotarem®, ProHance®, Gadovist®
CO2H
HO2C
HO2C
CO2H
N
N
N
H5dtpa
Magnevist®, Omniscan®, MultiHance®,
OptiMARK®, Eovist®, AngioMARK®
CO2H
CO2H
Struktura komplexů
[Gd(dota)] –
[Gd(dtpa)] 2–
r1 = f (q, M , R , MSS , T1,2e )
Bifunkční deriváty kyseliny fosfinové
s optimální hodnotou M 10 – 40 ns
I. Lukeš, J. Kotek, P. Vojtíšek, P. Hermann: Coord. Chem. Review, 2001, 216, 287-312
P. Vojtíšek, P. Cígler, J. Kotek, J. Rudovský, P. Hermann, I. Lukeš: Inorg. Chem., 2005, 44, 5591-9
J. Kotek, J. Rudovský, P. Hermann, I. Lukeš: Inorg. Chem., 2006, 45, 3097-3102
P. Hermann, J. Kotek, V. Kubíček, I. Lukeš : Dalton Trans., 2008, 3027-47
Bifunkční deriváty kyseliny fosfinové
s optimální hodnotou M 10 – 40 ns
OH
HO2C
N
N
OH
P
HO2C
N
N
O
HO2C
N
N
CO2H
H4do3aPABn
P
CO2H
O
NH2
HO2C
N
N
CO2H
H5do3aPPrA
vhodné pro konjugaci MRI kontrastních látek na makromolekulu
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, 455-465
M. Polášek, J. Kotek, P. Hermann, I. Císařová, K. Binneman, I. Lukeš: Inorg. Chem., 2009, 48, 466-475
r1 = f (q, M , R , MSS , T1,2e )
The chemical / physical features that affect R
Slow molecular tumbling
Immobilization of low-molecular Gd(III) complexes
Covalent – linear carrier, spheric carrier
Šplhání na vrchol reálného profilu
H5
r1
do3aPABn
PANAM konjugát
+ arginin
H5do3aPABn
PANAM
konjugát
H5dtpa,
H4dota
H5dt4aPABn
konjugát inulinu
– log(R)
H5do3aP
– log(M)
H6dt4aP
Synthesis of conjugates…
H2O, pH 8-9
CD-NH2 + L-NCS
40 °C, 24 h
O
OH
C
O
C
O
N
N
C
OH
OH
HO
N
OH
O
N
N
P
C
N
C
N
O
C
HO
O
O
HO
O
C
N
OH
HO
HN
P
S
O
C
S
OH
HN
N
P
C
O
N
NH
N
NH
C
N
O
OH
NH
C
O
O
OH
OH
HO
O
OH
N
O
HO
O
P
O
HO
HO
HO
O
O
O
O
C
S
HN
O
N
N
C
S
O
HN
O
C
OH
O
OH
C
P
O
O
C
N
N
N
HO
C
O
OH
N
N
HO
N
O
C
HO
C
O
P
OH
C
OH
N
N
HO
NH
N
O
S
C
O
C
OH
OH
NH
N
OH
O
HO
C
P
OH
HN
N
H
NH
O
HO
N
C
C
N
H
OH
N
HO
O
HO
OH
N
O
S
OH
C
OH
C
C
O
O
S
HO
O
O
HN
O
OH
O
1H
HOOC
NMRD profiles of Gd(III)DO3A-PBnN{CS}
conjugate with ß-cyclodextrine
N
N
P(O)
OH
HOOC
N
N
NH C
COOH
S
AB-bCD
25 °C
37 °C
35
30
r1 / s–1 mM –1
25
20
15
10
5
0
0.001
0.01
0.1
1
Proton Larmor Frequency / MHz
10
100
1000
Multimodal Probes
Dual Probes
Labelling of Cells
Distribution of the Cells in Organism
Dual Probes
PAMAM dendrimers conjugates
(a)
(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 GdIII) for 24 h. A typical size of the LIS is 300 μm.
MRI
Targeting
Gd
Similar strategy would be applied
for development of optical and
combined imaging probes.
Relaxometric parameters
of Gd(III)–DOTAPP and related ligands
O
PO3H2
Ligand
2
[1020 s–2]
298
v
298
RH
298
M
[ps]
[ps]
[ms]
r1
[s–1 mM–1]
DOTAPP
0.320.3
211
1354
1.000.08
6.17
BPAMD a
0.37
17
88
1.18
5.3
BPAPD b
1.22
27
85
1.1
5.0
DOTA c
0.16
11
77
0.244
4.8
HN
OH
PO3H2
N
N
N
N
O
HO
O
HO
O
O
H2O3P
NH
H2O3P
O
HO
N
N
N
N
HO
O
OH
O
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, 16477–16485.
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
Biodistribution
Biodistribution
of 177Lu-complexes in Lewis
rat 24 h after injection
Lu-c1
Lu-c3
SPECT/CT Imaging of Rats
177Lu-c1
75–80 MBq
1 h p.i.
24 h p.i.
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, 16477–16485.
PET
(110) min., 11C (20 min.) – cyclotron
Combination of PET and MRI, PET and CT
68Ga (60 min.), generator
18F
PET/CT imaging of osteoblastic bone metastases
with 68Ga-bisphosponates – First in human study
(a) = coronal PET, (b) = sagittal PET/CT. For comparison (c) shows 18F-fluoride PET.
University of Mainz, Zentral Klinik Bad Berka