Lothar Helm - Academia.edu (original) (raw)
Papers by Lothar Helm
The Journal of Chemical Physics, 2008
Contrast Media & Molecular Imaging, 2008
Gd 3 L is a trinuclear Gd 3R complex of intermediate size, designed for contrast agent applicatio... more Gd 3 L is a trinuclear Gd 3R complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H 12 L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine-N,N,N 00 ,N 00 -tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd 3 L has remarkable proton relaxivities at high magnetic field (r 1 ¼ 10.2 vs 3.0 mM S1 s S1 for GdDOTA at 9.4 T, 37-C, in H 2 O). Here we report an in vivo MRI feasibility study, complemented with dynamic g scintigraphic imaging and biodistribution experiments using the 153 Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd 3 L and the commercial contrast agent gadolinium(III)-1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd 3 L was well tolerated by the animals at the dose of 8 mmol Gd kg S1 body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd 3 L injection than after GdDOTA injection at an identical dose. The relaxation rates, DR 1 , were calculated from the IR TrueFISP data. During the excretory phase, the DR 1 for various tissues was similar for Gd 3 L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 mmol Gd kg S1 body weight). These results point to an approximately three times higher in vivo relaxivity (per (www.interscience.wiley.com) 78 Gd) for Gd 3 L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd 3 L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd 3 L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic g scintigraphic studies and the biodistribution experiments performed in Wistar rats with 153 Sm-enriched * Sm 3 L are also indicative of a fast elimination via the kidneys.
Metal ions in biological systems, 2003
Chimia, 2011
Magnetic resonance imaging (MRI) is one of the most powerful diagnostic techniques used in clinic... more Magnetic resonance imaging (MRI) is one of the most powerful diagnostic techniques used in clinics. The need for higher spatial resolution and better sensitivity led to the development of imagers working at high magnetic fields. The routine clinical use of 3 T MR systems raised the demand for MRI contrast agents working at this field or above. In the following we summarize the research in our research group on such high-field contrast agents.
Physical Chemistry Chemical Physics, 2000
We performed variable temperature (0È100 ¡C), concentration and frequency (9.425, 75, 150 and 225... more We performed variable temperature (0È100 ¡C), concentration and frequency (9.425, 75, 150 and 225 GHz) continuous wave electron paramagnetic resonance (EPR) measurements on three di †erent Gd(III) compounds :
Inorganic Chemistry Communications, 2002
A new global analysis of EPR, 17O NMR relaxation and chemical shift and 1H NMRD profiles with phy... more A new global analysis of EPR, 17O NMR relaxation and chemical shift and 1H NMRD profiles with physically meaningful parameters for [Gd(DOTA)(H2O)]− and for [Gd(DTPA)(H2O)]2− in aqueous solution is presented (DOTA=1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)-cyclododecane; DTPA=diethylenetriamine-N,N,N′,N″,N″-pentaacetic acid). The recent developments of an improved EPR relaxation theory, the inclusion of the internal motion of the bound water molecule are the principal modifications. Furthermore the better knowledge of the quadrupolar coupling constant of the bound water molecule, the neglect of the outer-sphere contribution to the chemical shift and the consideration of different isomers for the DOTA complex allowed for an improved analysis. The water exchange and parameters of rotational motion are only slightly changed. Comparison of the contributions of static zero-field-splitting shows that a more symmetric environment of the Gd(III) ion should lead to slower electron spin relaxation, a feature which can become important if all other parameters (rotational correlation time and water exchange rate) are optimised. In the actual stage the improved combined analysis of Gd(III) poly(amino carboxylate) is limited by the approximations of Redfield’s relaxation theory, i.e., very low frequency NMRD-data and slowly tumbling complexes cannot be analysed with the method presented.
Chemical Physics Letters, 2004
Ligand field effects in lanthanide ions compounds have consequences for optical and magnetic spec... more Ligand field effects in lanthanide ions compounds have consequences for optical and magnetic spectroscopy. In the analysis of electron paramagnetic resonance spectra of Gd3+ complexes, a major role is played by the zero field splitting (ZFS), which is a high order consequence of the ligand field and the spin–orbit coupling. We present a general parameterized method and a computer program for the study of the excited states of lanthanide complexes. We apply it for the first principles determination of the ZFS of the [Gd(H2O)8]3+ aqua ion and the corresponding EPR peak-to-peak width in solution. We calculate the influence of the various contributions to the effective Hamiltonian on the splitting of the ground state multiplet.
![Research paper thumbnail of Electronic fine structure calculation of [Gd(DOTA)(H2O)]– using LF-DFT: The zero field splitting](https://attachments.academia-assets.com/46608757/thumbnails/1.jpg)
](Comptes Rendus Chimie, 2012
Inorganic Chemistry - INORG CHEM, 1989
b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The ... more b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The red microcrystalline 3, which precipitated after 8 h, was filtered and vacuum-dried.
Inorganic Chemistry - INORG CHEM, 1992
Dimethylformamide (DMF) exchange on [Ti(DMF)6]3+ has been studied as a function of temperature (1... more Dimethylformamide (DMF) exchange on [Ti(DMF)6]3+ has been studied as a function of temperature (192-355 K) and pressure (up to 200 MPa, at two temperatures) by proton and oxygen-17 NMR spectroscopy at 4.7 and 9.4 T. The following kinetic parameters were obtained: ke1298 = (6.6 i 0.1) X lo4 s-I, AH' = 23.6 f 0.3 kJ mol-I, AS' = -73.6 & 1.1 J K-I mol-l, AV = -5.7 f 0.6 cm3 mol-l, and A@* = -( 1.3 f 0.6) X lo-* cm' mol-' MPa-l. The negative volume of activation suggests an associative interchange, I,, mechanism for the DMF exchange on titanium(III), and confirms the mechanistic changeover (from I, to I, , ) along the hexasolvated trivalent first-row transition-metal ions previously observed in water, dimethyl sulfoxide, and trimethyl phosphate.
Journal of The Chemical Society, Chemical Communications, 1984
The R ~ ( H ~ 0 ) ~ 2 + ' 3 + couple merits special attention as the only known low-spin... more The R ~ ( H ~ 0 ) ~ 2 + ' 3 + couple merits special attention as the only known low-spin d6-d5 pair among transition metal aqua ions. Approximate values of k for the self exchange reaction [reaction (l)] have been estimated by applying the Marcus cross relation to a series of ...
Inorganic Chemistry - INORG CHEM, 1989
b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The ... more b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The red microcrystalline 3, which precipitated after 8 h, was filtered and vacuum-dried.
Progress in Nuclear Magnetic Resonance Spectroscopy, 2006
Journal of the American Chemical Society, 1996
ABSTRACT
Journal of The American Chemical Society, 2005
Rigid chelates of high-molecular weight, [M(tpy-DTTA)2]6- (M = Fe, Ru), are obtained upon self-as... more Rigid chelates of high-molecular weight, [M(tpy-DTTA)2]6- (M = Fe, Ru), are obtained upon self-assembly around one M(II) ion of two terpyridine-based molecules substituted in the 4'-position with the polyaminocarboxylate diethylenetriamine-N,N,N'',N''-tetraacetate, tpy-DTTA4-. The protonation constants of tpy-DTTA4- (log K1 = 8.65(4), log K2 = 7.63(4), log K3 = 5.25(6), log K4 = 3.30(7)) and [Fe(tpy-DTTA)2]6- (log K1 = 8.40(4), log K2 = 7.26(4)) have been determined by potentiometry, 1H NMR and UV-vis titrations. The thermodynamic stability constant log K(GdL) of [Fe(tpy-DTTA)2Gd2(H2O)4] measured at 25 degrees C by potentiometry is 10.87. This relatively low value is due to the direct linkage of the polyaminocarboxylate part to the electron-withdrawing terpyridine. UV-vis absorbance spectra of [M(tpy-DTTA)2Gd2(H2O)4] and 1H NMR spectra of [M(tpy-DTTA)2Eu2(H2O)4] revealed similar solution behavior of the Fe and Ru complexes. An I(d) water-exchange mechanism (DeltaV++ = +6.8 +/- 1 cm3 mol(-1)) with a rate constant of k(ex)298 = (5.1 +/- 0.3) x 10(6) s(-1) has been found for [Fe(tpy-DTTA)2Gd2(H2O)4] by 17O NMR. A slow rotational correlation time (tau(RO) = 410 +/- 10 ps) and the presence of two water molecules (q = 2) in the coordination inner-sphere of each Gd(III) ion have also been determined for this complex. A remarkably high relaxivity has been observed for both [M(tpy-DTTA)2Gd2(H2O)4] complexes (at 20 MHz and 37 degrees C, r(1) = 15.7 mM(-1) s(-1) for the Fe complex, and r(1) = 15.6 mM(-1) s(-1) for the Ru complex).
Inorganic Chemistry, 1992
Helvetica Chimica Acta, 1987
ABSTRACT
Helvetica Chimica Acta, 1984
ABSTRACT
Helvetica Chimica Acta, 1985
ABSTRACT
The Journal of Chemical Physics, 2008
Contrast Media & Molecular Imaging, 2008
Gd 3 L is a trinuclear Gd 3R complex of intermediate size, designed for contrast agent applicatio... more Gd 3 L is a trinuclear Gd 3R complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H 12 L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine-N,N,N 00 ,N 00 -tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd 3 L has remarkable proton relaxivities at high magnetic field (r 1 ¼ 10.2 vs 3.0 mM S1 s S1 for GdDOTA at 9.4 T, 37-C, in H 2 O). Here we report an in vivo MRI feasibility study, complemented with dynamic g scintigraphic imaging and biodistribution experiments using the 153 Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd 3 L and the commercial contrast agent gadolinium(III)-1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd 3 L was well tolerated by the animals at the dose of 8 mmol Gd kg S1 body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd 3 L injection than after GdDOTA injection at an identical dose. The relaxation rates, DR 1 , were calculated from the IR TrueFISP data. During the excretory phase, the DR 1 for various tissues was similar for Gd 3 L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 mmol Gd kg S1 body weight). These results point to an approximately three times higher in vivo relaxivity (per (www.interscience.wiley.com) 78 Gd) for Gd 3 L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd 3 L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd 3 L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic g scintigraphic studies and the biodistribution experiments performed in Wistar rats with 153 Sm-enriched * Sm 3 L are also indicative of a fast elimination via the kidneys.
Metal ions in biological systems, 2003
Chimia, 2011
Magnetic resonance imaging (MRI) is one of the most powerful diagnostic techniques used in clinic... more Magnetic resonance imaging (MRI) is one of the most powerful diagnostic techniques used in clinics. The need for higher spatial resolution and better sensitivity led to the development of imagers working at high magnetic fields. The routine clinical use of 3 T MR systems raised the demand for MRI contrast agents working at this field or above. In the following we summarize the research in our research group on such high-field contrast agents.
Physical Chemistry Chemical Physics, 2000
We performed variable temperature (0È100 ¡C), concentration and frequency (9.425, 75, 150 and 225... more We performed variable temperature (0È100 ¡C), concentration and frequency (9.425, 75, 150 and 225 GHz) continuous wave electron paramagnetic resonance (EPR) measurements on three di †erent Gd(III) compounds :
Inorganic Chemistry Communications, 2002
A new global analysis of EPR, 17O NMR relaxation and chemical shift and 1H NMRD profiles with phy... more A new global analysis of EPR, 17O NMR relaxation and chemical shift and 1H NMRD profiles with physically meaningful parameters for [Gd(DOTA)(H2O)]− and for [Gd(DTPA)(H2O)]2− in aqueous solution is presented (DOTA=1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)-cyclododecane; DTPA=diethylenetriamine-N,N,N′,N″,N″-pentaacetic acid). The recent developments of an improved EPR relaxation theory, the inclusion of the internal motion of the bound water molecule are the principal modifications. Furthermore the better knowledge of the quadrupolar coupling constant of the bound water molecule, the neglect of the outer-sphere contribution to the chemical shift and the consideration of different isomers for the DOTA complex allowed for an improved analysis. The water exchange and parameters of rotational motion are only slightly changed. Comparison of the contributions of static zero-field-splitting shows that a more symmetric environment of the Gd(III) ion should lead to slower electron spin relaxation, a feature which can become important if all other parameters (rotational correlation time and water exchange rate) are optimised. In the actual stage the improved combined analysis of Gd(III) poly(amino carboxylate) is limited by the approximations of Redfield’s relaxation theory, i.e., very low frequency NMRD-data and slowly tumbling complexes cannot be analysed with the method presented.
Chemical Physics Letters, 2004
Ligand field effects in lanthanide ions compounds have consequences for optical and magnetic spec... more Ligand field effects in lanthanide ions compounds have consequences for optical and magnetic spectroscopy. In the analysis of electron paramagnetic resonance spectra of Gd3+ complexes, a major role is played by the zero field splitting (ZFS), which is a high order consequence of the ligand field and the spin–orbit coupling. We present a general parameterized method and a computer program for the study of the excited states of lanthanide complexes. We apply it for the first principles determination of the ZFS of the [Gd(H2O)8]3+ aqua ion and the corresponding EPR peak-to-peak width in solution. We calculate the influence of the various contributions to the effective Hamiltonian on the splitting of the ground state multiplet.
Comptes Rendus Chimie, 2012
Inorganic Chemistry - INORG CHEM, 1989
b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The ... more b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The red microcrystalline 3, which precipitated after 8 h, was filtered and vacuum-dried.
Inorganic Chemistry - INORG CHEM, 1992
Dimethylformamide (DMF) exchange on [Ti(DMF)6]3+ has been studied as a function of temperature (1... more Dimethylformamide (DMF) exchange on [Ti(DMF)6]3+ has been studied as a function of temperature (192-355 K) and pressure (up to 200 MPa, at two temperatures) by proton and oxygen-17 NMR spectroscopy at 4.7 and 9.4 T. The following kinetic parameters were obtained: ke1298 = (6.6 i 0.1) X lo4 s-I, AH' = 23.6 f 0.3 kJ mol-I, AS' = -73.6 & 1.1 J K-I mol-l, AV = -5.7 f 0.6 cm3 mol-l, and A@* = -( 1.3 f 0.6) X lo-* cm' mol-' MPa-l. The negative volume of activation suggests an associative interchange, I,, mechanism for the DMF exchange on titanium(III), and confirms the mechanistic changeover (from I, to I, , ) along the hexasolvated trivalent first-row transition-metal ions previously observed in water, dimethyl sulfoxide, and trimethyl phosphate.
Journal of The Chemical Society, Chemical Communications, 1984
The R ~ ( H ~ 0 ) ~ 2 + ' 3 + couple merits special attention as the only known low-spin... more The R ~ ( H ~ 0 ) ~ 2 + ' 3 + couple merits special attention as the only known low-spin d6-d5 pair among transition metal aqua ions. Approximate values of k for the self exchange reaction [reaction (l)] have been estimated by applying the Marcus cross relation to a series of ...
Inorganic Chemistry - INORG CHEM, 1989
b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The ... more b) From 2. A solution of 223 mg (0.216 mmol) of 2 in 10 mL of toluene was saturated with CO. The red microcrystalline 3, which precipitated after 8 h, was filtered and vacuum-dried.
Progress in Nuclear Magnetic Resonance Spectroscopy, 2006
Journal of the American Chemical Society, 1996
ABSTRACT
Journal of The American Chemical Society, 2005
Rigid chelates of high-molecular weight, [M(tpy-DTTA)2]6- (M = Fe, Ru), are obtained upon self-as... more Rigid chelates of high-molecular weight, [M(tpy-DTTA)2]6- (M = Fe, Ru), are obtained upon self-assembly around one M(II) ion of two terpyridine-based molecules substituted in the 4'-position with the polyaminocarboxylate diethylenetriamine-N,N,N'',N''-tetraacetate, tpy-DTTA4-. The protonation constants of tpy-DTTA4- (log K1 = 8.65(4), log K2 = 7.63(4), log K3 = 5.25(6), log K4 = 3.30(7)) and [Fe(tpy-DTTA)2]6- (log K1 = 8.40(4), log K2 = 7.26(4)) have been determined by potentiometry, 1H NMR and UV-vis titrations. The thermodynamic stability constant log K(GdL) of [Fe(tpy-DTTA)2Gd2(H2O)4] measured at 25 degrees C by potentiometry is 10.87. This relatively low value is due to the direct linkage of the polyaminocarboxylate part to the electron-withdrawing terpyridine. UV-vis absorbance spectra of [M(tpy-DTTA)2Gd2(H2O)4] and 1H NMR spectra of [M(tpy-DTTA)2Eu2(H2O)4] revealed similar solution behavior of the Fe and Ru complexes. An I(d) water-exchange mechanism (DeltaV++ = +6.8 +/- 1 cm3 mol(-1)) with a rate constant of k(ex)298 = (5.1 +/- 0.3) x 10(6) s(-1) has been found for [Fe(tpy-DTTA)2Gd2(H2O)4] by 17O NMR. A slow rotational correlation time (tau(RO) = 410 +/- 10 ps) and the presence of two water molecules (q = 2) in the coordination inner-sphere of each Gd(III) ion have also been determined for this complex. A remarkably high relaxivity has been observed for both [M(tpy-DTTA)2Gd2(H2O)4] complexes (at 20 MHz and 37 degrees C, r(1) = 15.7 mM(-1) s(-1) for the Fe complex, and r(1) = 15.6 mM(-1) s(-1) for the Ru complex).
Inorganic Chemistry, 1992
Helvetica Chimica Acta, 1987
ABSTRACT
Helvetica Chimica Acta, 1984
ABSTRACT
Helvetica Chimica Acta, 1985
ABSTRACT