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Journal ArticleDOI

153Sm3+ and 111In3+ DTPA derivatives with high hepatic specificity: in vivo and in vitro studies

25 Jul 2002-Journal of Inorganic Biochemistry (Elsevier)-Vol. 91, Iss: 1, pp 312-319

TL;DR: Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp and the ligand DTPA(BOM) 3, were studied as potential hepatospecific gamma scintigraphic agents, showing that the main excretory pathway for all the chelates studied is the hepatobiliary system.

AbstractTwo DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L 1 ) and the ligand DTPA(BOM) 3 (BOM=benzyloxymethyl) (L 2 ), radiolabelled with 153 Sm 3+ and 111 In 3+ , were studied as potential hepatospecific gamma scintigraphic agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The complexes of L 2 show even greater hepatobiliary specificity than L 1 , perhaps as a consequence of longer blood circulation times due to their strong affinity towards HSA. The 153 Sm 3+ chelates are also more hepatospecific than the corresponding 111 In 3+ chelates. The La 3+ and In 3+ chelates of L 1 and L 2 show some structural and dynamic differences in aqueous solution, as studied by 1 H NMR spectroscopy. While only two nona-coordinated isomers were observed for the La 3+ complexes with both ligands, its number is much larger in the In 3+ complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination number.

Summary (1 min read)

Jump to:  and [1 . Introduction]

1 . Introduction

  • The Gd(III) complexes of both ligands, which have The primary objective of their work was to perform already been characterised [4] [5] [6] , show a high binding 31 biodistribution studies and obtain information about affinity to HSA, in particular Gd -L [6] .
  • Experimental carrier-mediated pathway, in common with taurocholate but not conjugated bilirubin [9], operated by the human 2 .1.
  • Reagents and apparatus liver organic anion transporting polypeptide (OATP) [12] .

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Journal of Inorganic Biochemistry 91 (2002) 312319
www.elsevier.com/locate/jinorgbio
153 31 111 31
Sm and In DTPA derivatives with high hepatic specificity: in
vivo and in vitro studies
a,b,c a d b,c, a
*
M.I.M. Prata , A.C. Santos , M. Neves , C.F.G.C. Geraldes , J.J.P. de Lima
a
´´
Servic¸o de Biof ısica e Biomatematica
,
Faculdade de Medicina
,
Universidade de Coimbra
, 3001
-
401
Coimbra
,
Portugal
b
´ˆ
Departamento de Bioquımica
,
Faculdade de Ciencias e Tecnologia
,
Universidade de Coimbra
,
Apartado
3126, 3001
-
401
Coimbra
,
Portugal
c
ˆ
Centro de Neurociencias
,
Universidade de Coimbra
, 3001
-
401
Coimbra
,
Portugal
d
´´
Instituto Tecnologico e Nuclear
, 2686
-
953
Sacavem
,
Portugal
Received 17 October 2001; received in revised form 4 February 2002; accepted 6 March 2002
Abstract
Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L ) and the ligand DTPA(BOM)
13
153 31 111 31
(BOM5benzyloxymethyl) (L ), radiolabelled with Sm and In , were studied as potential hepatospecific gamma scintigraphic
2
agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The
complexes of L show even greater hepatobiliary specificity than L , perhaps as a consequence of longer blood circulation times due to
21
153 31 111 31 31
their strong affinity towards HSA. The Sm chelates are also more hepatospecific than the corresponding In chelates. The La
31 1
and In chelates of L and L show some structural and dynamic differences in aqueous solution, as studied by H NMR spectroscopy.
12
31 31
While only two nona-coordinated isomers were observed for the La complexes with both ligands, its number is much larger in the In
complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination
number. 2002 Elsevier Science Inc. All rights reserved.
Keywords
:
Hepatic specificity; 153-Samarium; DTPA derivatives; 111-Indium
1 . Introduction derivatives, a mono-amide derivative containing an
iopanoic acid as iodinated synthon, DTPA-IOPsp,
Nuclides of indium-111 and samarium-153 have found h11,14,17-tris-(carboxymethyl)-1-(5-(1-carboxy-2-ethyl-
153
widespread use in nuclear medicine. Sm is a b- and propyl)-2,4,6-triiodo-phenyl)-2,9-bis-carbonyl-1,8,11,
g-emitter with a half-life of 1.9 days [1], which is currently 14, 17 - pentaazaj-nonadecan - 19 - oic acid (L ), and
1
153
used in the common form of SmEDTMP (EDTMP DTPA(BOM) (BOM5benzyloxymethyl), h4-carboxy-5,8-
3
stands for ethylenediamino-tetramethylenephosphonate) as bis - (carboxymethyl)-1-phenyl - 8,11 - bis(1 - carboxy - 2-
a palliative agent for painful bone metastasis [2]. These benzyloxymethyl-ethyl)-2-oxa - 5,8,11 - triazaj-tridecan-13-
two radionuclides present suitable chemical properties for —oic acid (L ) (see Fig. 1). Ligand L was used as a
22
in vivo applications: only the 13 oxidation state occurs in mixture containing random populations of the absolute R
water and its aqueous chemistry is dominated by its strong and S configurations for the three chiral carbons present.
Lewis acidity and oxophilicity [3]. The Gd(III) complexes of both ligands, which have
The primary objective of our work was to perform already been characterised [46], show a high binding
31
biodistribution studies and obtain information about affinity to HSA, in particular Gd L [6]. Furthermore,
2
31
biokinetics, clearance and in vivo stability in Wistar rats of the Gd L complex is preferentially eliminated via the
1
153 31 111 31
complexes of Sm and In with two DTPA hepatobiliary pathway (65% biliary elimination in rats
after 8 h [4]). The established hepatobiliary contrast
agents, Gd(BOPTA) (Multihance, Bracco) and Gd(EOB-
*
Corresponding author. Tel.: 1351-2-3982-4531; fax: 1351-2-3985-
DTPA) (Eovist, Schering), were found to undergo .35%
3607.
E-mail address
:
geraldes@ci.uc.pt (C.F.G.C. Geraldes). biliary excretion and to enter the hepatocytes via a
0162-0134/02/$ see front matter 2002 Elsevier Science Inc. All rights reserved.
PII: S0162-0134(02)00417-8

M
.
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.
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/ Journal of Inorganic Biochemistry
91 (2002) 312
319
313
Fig. 1. Chemical structures of the ligands (a) L , (b) L .
12.
1
combination of passive diffusion and a carrier-mediated L complexes are compared by H NMR. Any differences
2
mechanism [79], shared with conjugated bilirubin, and between the various metal complexes of the same ligand
involving an organic anion transporter [10], which has with the two ions may be reflected in different in vivo
153 31 111 31
been found to be the plasma membrane ABC protein behaviour of their Sm and In complexes.
cMOAT/mrp2 [11]. However, a recent study of the
31
transport mechanism of Gd L through hepatocytes
1
indicates that its biliary excretion occurs via a different 2 . Experimental
carrier-mediated pathway, in common with taurocholate
but not conjugated bilirubin [9], operated by the human
2 .1.
Reagents and apparatus
liver organic anion transporting polypeptide (OATP) [12].
111
The enhanced liver uptake of this compound is due to three InCl in 0.8 N HCl (specific activity 0.4 GBq/ml)
3
main factors, the presence of the iopanoic acid moiety, the was obtained from CIS-Biointernational (Saclay, France).
lipophilicity and the charge distribution on the molecule, 153-Samarium oxide was produced at the ITN (Instituto
´
but the presence of the iopanoic moiety is crucial [4]. Tecnologico e Nuclear), Lisbon with a specific activity .5
However a contrast agent used in MRI should be adminis- GBq/mg. The chromatographic paper used in the quality
tered in much higher concentrations than a radiophar- control (3MM Chr Whatman) was obtained from W.&R.
maceutical used in nuclear medicine. Since the in vivo Balston, UK. The two ligands used in this work were
behaviour of a complex can be metal- and dose-dependent, synthesized and characterised as described elsewhere [4,5]
the current studies were undertaken in order to elucidate and kindly provided by Dr. P.A. Anelli from Bracco,
the relationships of structure and concentration with activi- Milan, Italy. Other reagents and solvents were obtained
ty, which govern the biodistribution and pharmacokinetics from either Aldrich or Sigma (Madrid, Spain) and used as
of these metal chelates. received. All reagents to be used in vivo were prepared
31
As far as we know, the In complexes of these two sterile and pyrogen free.
ligands have not yet been characterised. The different ionic A gamma camera-computer system (GE 400 GenieAcq,
31 31 31
˚˚
radii of the In and Ln ions (0.81 A for In , 1.216 A from General Electrics, Milwaukee, USA) was used for
31 31
˚
for La and 1.032 A for Lu [13]) are reflected in the acquisition and pre-processing. Data processing and dis-
different coordination numbers of their polyaminocarbox- play were performed on a personal computer using
ylate complexes. In this work, the solution structures and homemade software developed for the IDL 5.2 computer
31 31 31 31
dynamics of the In L , In L , La L and La tool. A well-counter (DPC-Gamma C , LA, USA) with a
12 1 12

314 M
.
I
.
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Prata et al
.
/ Journal of Inorganic Biochemistry
91 (2002) 312
319
Compaq DeskPro compatible computer was used for These solutions were incubated with 2 ml of the HSA
activity counting in the biodistribution studies. The gamma solution and were continuously stirred for 6 h at 37 8C and
camera has been previously calibrated for each radio- then left overnight at room temperature. Samples were
isotope. finally ultrafiltrated through Centricon filters (from
Amicon, France) and activity counted both in the ultrafil-
2 .2.
Preparation of
153
-samarium oxide trate and the protein bound portions. The percentage of
protein bound compounds was calculated using the equa-
153
The Sm oxide was prepared from a 98% enriched tion:
target, sealed into a quartz vial and welded into an
% protein bound
aluminium can, by neutron irradiation using a thermal flux
13 2
5 100 3 [counts in labeled protein/
of 2.3310 n/cm s. Following irradiation the sample
(counts in labeled protein 1 counts in ultrafiltrate)].
was opened, dissolved in 1 N HCl and brought to a stock
23
concentration of 1.9310 M.
2 .6.
Gamma imaging
2 .3.
NMR studies
153
A stock solution of SmCl was prepared by dissolv-
3
153 111
ing Sm O in 0.1 M HCl. InCl was used as received.
For the NMR studies, complexes were prepared in D O
23 3
2
Stock solutions of the ligands were prepared in isotonic
(99.8% D) solutions at 5 mM concentrations, by adding
HEPES pH ca. 7 buffer and mixed (in a 1:1 mole ratio,
stoichiometric amounts of the ligands to stock solutions of
with 50% ligand excess) with the metal chlorides. The final
indium(III) nitrate and lanthanum(III) chloride. The pD of
pH was adjusted to 7.0 with diluted solutions of NaOH.
the solutions was adjusted with DCl and CO -free NaOD
2
The radiochemical purity was determined by chromatog-
using a Crison MicropH 2002 pH-meter with an Ingold
raphy using 3MM Whatman chromatography paper de-
405-M5 combined electrode (Crison Instruments, Bar-
veloped with a mixture of NH /EtOH/H O (in the ratio
celona, Spain) and converted to pH values using the
32
1
0.1 ml/2 ml/4 ml, respectively) analysing 2 ml of each
isotopic correction pH5pD20.4. H NMR spectra were
solution of the complex. With this system, the free metal
recorded at 25 8C, on a Varian UNITY-500 spectrometer
ion stays at the origin while the labelling product migrates
(Varian, Palo Alto, USA) at an external field of 11.8 T,
1
to R 50.9. The dried strips were cut into 1 cm pieces and
operating at 499.84 Hz. The H resonance shifts were
f
1
counted in a g well counter. For all the complexes, the
measured relative to the H water signal set at 4.74 ppm.
percentage of bound metal averaged 98%.
Assignments of the proton NMR spectra were based on
Gamma images and the biological distribution were
literature data for similar systems and in the results of
determined for all the complexes using 300-g Wistar rats.
two-dimensional homonuclear correlation spectra (COSY).
All animal studies were carried out in compliance with
procedures approved by the appropriate institutional re-
2 .4.
Partition coefcients
view committees. Conscious rats were allowed free access
111
of food and water ad libitum. Four groups of three animals
InL was prepared in distilled water by mixing the
1
111
(one group for each complex) were anaesthetised with
ligand with InCl (in a 10:1 molar ratio) and adjusting
3
ketamine (50 mg/ml)/chloropromazine (2.5%) (10:3).
the pH to ca. 7 with 0.1 M NaOH. The partition coefficient
111 31
was determined by addition of 25 ml of In -chelate
153
2 .6.1.
SmL studies
solution in a test tube containing 1 ml of saline solution
Wistar rats were injected in the femoral vein with ca.
and 1 ml of 1-octanol. The tubes were vortexed and
153 31
400 mCi of the respective Sm chelate. The animals
centrifuged for 3 min at 3000 rev./min. Then, 100-ml
were positioned in dorsal decubitus over the detector.
aliquots of each phase were taken for radioactivity count-
ing. The partition coefficients were calculated by dividing
111
the net radioactivity counting of the organic phase by that
2 .6.2.
InL studies
of the aqueous phase. The results presented are the means
Wistar rats were injected in the femoral vein with ca.
111 31
of five determinations (with a S.D.,0.01).
150 mCi of the respective In chelate. The animals
were positioned in ventral decubitus over the detector.
2 .5.
Protein binding
For both the radionuclides, image acquisition was
initiated immediately before radiotracer injection. Se-
Albumin solutions were freshly prepared by dissolving
quences of 180 images (10 s each) were acquired to
HSA in 0.1 M HEPES buffer to obtain 0.6 mM con-
64364 matrices.
centration (assuming 69 kDa as the HSA molecular weight
In order to analyse the transport of radiotracer over time,
[14]). L and L water solutions (0.2 mM) were labeled
five regions of interest (RI) were drawn on the image files,
12
111
with a small amount of InCl (in 0.1 N HCl), and then
corresponding to the thorax, liver, brain, intestines and left
3
InCl (non-radioactive) was added to obtain a 1:1 complex.
kidney. From these RI, timeactivity curves were obtained
3

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.
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.
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Prata et al
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/ Journal of Inorganic Biochemistry
91 (2002) 312
319
315
31
using an IDL-based program (Interactive Data Language, (instead of the paramagnetic Sm L complexes) to study
1
Research Systems, Boulder, CO, USA), which enables the their structure and dynamics in aqueous solution by H
31
RI’s drawing and calculates the activity per pixeltime NMR, and compare with the corresponding In L che-
curves. In addition, static data were acquired at 24 and 48 lates. The spectra (excluding the aromatic region) of the
h after the radiotracer injection. 1:1 complexes at pH 7.0 are shown in Fig. 2. Assignments
were based on published results on similar systems [15
2 .7.
Biodistribution experiments 18] and on the two-dimensional homonuclear correlation
spectra (COSY) obtained (see Fig. 1S in Supporting
Groups of four animals were injected in the femoral vein information).
111 31 153 31 31 31
with ca. 100 mCi of the two In or Sm complexes The spectra of the La L and In L complexes
11
and sacrificed 5, 15 and 30 min later. The major organs (Fig. 2a and c, respectively) are fairly similar, but the latter
31
were removed, weighed and counted in a g well counter. is sharper. Assuming that the La L complex is
1
2
Similar biodistribution studies were also performed with [La(DTPA-IOPsp)(H O)] and the ligand is bound as
2
31
the rats referred to in the previous section sacrificed at 48 DTPA or DTPA bis-amides [1518], the La ion is
h. nona-coordinated, by the three amine nitrogen atoms, five
oxygen atoms of the carboxylates and the amide carbonyl
group, and one oxygen of the water molecule, forming a
3 . Results and discussion tri-capped trigonal prismatic coordination polyhedron. Two
chiral centers are present in the ligand backbone (the
3 .1.
NMR studies central nitrogen and the terminal one next to the amide
group), leading to a maximum of two diastereomeric pairs
Since the complexes of the whole series of lanthanide of enantiomers, and two observable sets of proton reso-
31
ions with a variety of DTPA derivatives are isostructural nances. This is observed in the spectrum of La L ,
1
31
[1517], the diamagnetic La L complexes were chosen where many of the proton signals from the amide sub-
1 31 31 31
Fig. 2. H NMR spectra of the 1:1 complexes in D O. Metal and ligand concentration 10 mM, pH 7.0: (a) La L , (b) La L , (c) In L , (d)
2 121
31
In L .
2

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.
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Prata et al
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/ Journal of Inorganic Biochemistry
91 (2002) 312
319
stituent group are doubled, such as those of the iopanoic major isomers (out of the four possible) are present in
acid moiety, as shown by the COSY spectrum. The shift
solution for this chelate. The CH protons of the BOM
2
differences observed for the same protons in the two
groups directly attached to the a carbons at the substituted
diastereomers of such a diamagnetic complex are very
acetate arms, coupled to the a CH protons, give five
small. At least seven AB patterns are also seen in the
different pairs of coupled quartets (AB parts of ABX
3.83.2 ppm region, corresponding to the five bound
systems), while the BOM CH protons next to the benzene
2
acetate and amide methylene groups of the ligand, as
ring give at least eight singlet resonances (two major ones).
defined by their COSY cross-peaks [18]. The observation
This large number of resonances indicates that the chirality
of broad resonances for the eight CH protons of the
at the a carbons may affect the shifts of those protons,
2
ligand backbone (at 2.82.3 ppm) and for two of the AB
located very close to the chirality center.
31
patterns of acetate methylene groups (at 3.73.5 ppm)
The In L spectrum (Fig. 2d) is very complex (up to
2
indicates that the dynamics of the interchange of the
40 COSY cross-peaks), making any quantitative interpreta-
isomers present in the complex, e.g. by racemization of the
tions impossible. The observation of at least three major
central nitrogen [16], is relatively slow.
AB patterns from the CH protons at the non-substituted
2
31
The In L spectrum (Fig. 2c) shows at least two
bound acetate arms, and the large number (at least 17) of
1
signals for each proton of the amide substituent group, but
resonances for the backbone and BOM CH protons close
2
its aromatic proton, instead of a sharp singlet, has four
to the benzene ring, show that the number of major
components, two intense and two weaker. Many more
isomers is larger and/or more asymmetric than for the
31 31
acetate and amide CH proton AB patterns, at 3.83.2
La complex. The In complex again has both octa- and
2
ppm, and backbone CH sharp multiplets, at 3.42.8 ppm,
hepta-coordinated species, as well as various isomers for
2
31
are observed than in the spectrum of La L . All these
each coordination number.
1
observations indicate that the isomeric equilibrium is more
31 31
complex in In L than in La L , with both octa- and
11
3 .2. 1
-Octanol/saline partition coefcients and
hepta-coordinated (with an unbound amide or acetate side
interaction with HSA
arm) species, as well as structural isomers for each
coordination number, giving multiple signals of different
111 31 153 31
In L and Sm L give, at pH 7, an octanol/
intensities for each proton. This is in agreement with
11
31
water log P value of 21.65 and 21.15, indicating a low
previous studies of In -DTPA-bis(amides) [18].
31
lipophilicity for these complexes. Given the high hepato-
The complexity of the spectra of the La L and
2
31
biliary excretion observed for these chelates (see later), this
In L complexes (Fig. 2b and d) makes a detailed
2
result illustrates once again that lipophilicity is not the
analysis impossible, even with COSY spectra. They are
main factor determining the excretion pathway of a
sharp but quite different, indicating structural differences.
31 22
substance. One would expect high log P values for the
If the La L complex is [La(DTPA-(BOM) )(H O)] ,
232
complexes of L , as a consequence of the presence of the
with the ligand bound as DTPA or DTPA bis-amides
2
31
three aromatic groups in its chelates, but this value was
[1518], again with a nona-coordinated La ion in a
153 31
22.60 for Sm L and was not determined ex-
tri-capped trigonal prismatic coordination polyhedron, the
2
111 31
ligand backbone has three chiral centers (the three nitro- perimentally for In L .
2
111 31
gens), originating a maximum of four diastereomeric pairs The complexes of In with both ligands bind
of enantiomers [16]. Fast racemization of the middle efficiently to HSA, as shown by the values obtained for the
31
nitrogen usually leads to four resonances at room tempera- percentage of protein-bound In chelates, 92% for
111 31 111 31
ture for each type of proton. The chirality in the benzylox- In L and 97% for In L . Although these
12
ymethyl (BOM) chains originates another three chiral values might be slightly overestimated, and perhaps need
centers and a total of 32 diastereomeric pairs of enantio- confirmation by other methodologies, they are in quali-
mers. The corresponding multiplication of signals is usual- tative agreement with literature HSA binding data for the
31
ly not observable in the NMR spectra of diamagnetic Gd complexes of these ligands. It has been reported that
31
complexes, due to the very small proton shift differences, Gd L binds strongly to human serum [4], and the
1
22
as is the case for the [Ln(BOPTA)(H O)] (BOPTA; values reported in the literature for the association con-
2
31
DTPA-(BOM)) complexes [19]. stants of the Gd complexes to HSA are quite high:
31 3 2131
The La L spectrum (Fig. 2b) shows five distinct K 54.8310 M for the Gd L complex [20] and
2a1
4 2131
regions, corresponding to the different types of ligand especially K 54.0310 M for the Gd L complex
a2
protons. The aromatic moieties give multiple signals, [6], a value quite similar to that of MS-325 [21]. In fact,
31
indicating the presence of various isomers. The COSY binding of Gd complexes to HSA has been promoted by
spectrum (see Supporting information) allows assignment the presence of hydrophobic synthons of known high
of some resonances, such as two intense AB patterns, affinity to the serum proteins. An example is a series of
corresponding to the CH protons at the non-substituted DTPA- and DOTA-like complexes bearing iopanoic acid
2
bound acetate arms. This clearly indicates that only two residues linked through an amidic bond [20], such as

Citations
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Journal ArticleDOI
TL;DR: These studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions.
Abstract: {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd3+ centers confined into a small mol. space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r1 = 15.8 mM-1 s-1 at 200 MHz, 37°C, in H2O). Here we report the first in vivo MRI feasibility study, complemented with dynamic g scintigraphic imaging and biodistribution expts. using the 153Sm-enriched compd. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small mol. wt. contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H2O)]- = GdDOTA). The metallostar was well tolerated by the animals at the concns. of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg-1 body wt.; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg-1 BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T1), as calcd. from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approx. four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate mol. wt., the metallostar does not function as a blood pool agent. The dynamic g scintigraphic studies performed in Wistar rats with the metallostar compd. having 153Sm enrichment also proved the renal elimination pathway. The biodistribution expts. are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.

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Journal ArticleDOI
TL;DR: The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are indicative of a fast elimination via the kidneys, and the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions.
Abstract: Gd(3)L is a trinuclear Gd(3+) 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'',N''-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) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma 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)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) 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, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(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 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per 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 gamma 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.

34 citations


Cites methods from "153Sm3+ and 111In3+ DTPA derivative..."

  • ...In order to gain further insight into the in vivo behaviour of the trinuclear Gd3L, we performed biodistribution and dynamic g scintigraphic studies in Wistar rats using the Sm3þ analog complex where the gadolinium was replaced by a mixture of radioactive ((153)Sm) and non-radioactive samarium (22,23)....

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Journal ArticleDOI
TL;DR: The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.
Abstract: A novel bis-hydroxymethyl-substituted DTTA chelatorN′-Bz-C4,4′-(CH2OH)2-DTTA (1) and its DTPA analogue C4,4′-(CH2OH)2-DTPA (2) were synthesized and characterized. A variable-temperature 1H NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln3+ complexes showed them to be rigid when compared with analogous Ln3+-DTTA and Ln3+-DTPA complexes, as a result of their C4,4′-(CH2OH)2 ligand backbone substitution. The parameters that govern the water1H relaxivity of the [Gd(1)(H2O)2]− and [Gd(2)(H2O)]2− complexes were obtained by 17O and 1H NMR relaxometry. While the relaxometric behaviour of the [Gd(2)(H2O)]2− complex is very similar to the parent [Gd(DTPA)(H2O)]2− system, the [Gd(1)(H2O)2]− complex displays higher relaxivity, due to the presence of two inner sphere water molecules and an accelerated, near optimal water exchange rate. The [Gd(1)(H2O)2]− complex interacts weakly with human serum albumin (HSA), and its fully bound relaxivity is limited by slow water exchange, as monitored by 1H NMR relaxometry. This complex interacts weakly with phosphate, but does not form ternary complexes with bidentate bicarbonate and L-lactate anions, indicating that the two inner-sphere water molecules of the [Gd(1)(H2O)2]− complex are not located in adjacent positions in the coordination sphere of the Gd3+ ion. The transmetallation reaction rate of [Gd(1)(H2O)2]− with Zn2+ in phosphate buffer solution (pH 7.0) was measured to be similar to that of the backbone unsubstituted [Gd(DTTA-Me)(H2O)2]−, but twice faster than for [Gd(DTPA-BMA)(H2O)]. The in vivo biodistribution studies of the 153Sm3+-labelled ligand (1) in Wistar rats reveal slow blood elimination and short term fixation in various organs, indicating some dissociation. The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.

20 citations


Journal ArticleDOI
TL;DR: This review discusses radiotheranostics with radiolanthanides, focusing on the design, development strategies, and medical applications of radiolAnthanide-labeled probes.
Abstract: “Radiotheranostics” is a term used in nuclear medicine to refer to the use of radioisotope (RI)-labeled agents to perform simultaneous imaging and therapy of a target lesion. A radiotheranostics system uses radiolanthanides as diagnostic and therapeutic RIs. In this review, we discuss radiotheranostics with radiolanthanides, focusing on the design, development strategies, and medical applications of radiolanthanide-labeled probes. We also discuss the potential and future uses of radiolanthanides in radiotheranostics.

15 citations


References
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Abstract: This 2-volume work contains nuclear structure and decay data for over 3,100 isotopes and isomers. Features: References data from thousands of pages of figures and tables. Encompasses about twice as much data as the previous edition. The extensive appendices have been entirely rewritten, expediting retrieval and use of nuclear information for many areas of research, and for users with varying levels of expertise.

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Book
19 Feb 2013
TL;DR: This paper presents physical principles of Medical Imaging by Nuclear Magnetic Resonance and EPR Methods in Contrast Agent Research: Examples from GdA+ Chelates, a comparison of Frequency and Frequency Aspects of Lanthanide(III) Complexes.
Abstract: Contributors. Preface. Physical Principles of Medical Imaging by Nuclear Magnetic Resonance (S. Mansson and A. Bjornerud). Relaxivity of Gadolinium (III) Complexes: Theory and Mechanism (E. Toth, et al.). Synthesis of MRI Contrast Agents I: Acyclic Ligands. (P. Anelli and L. Lattuada). Synthesis of MRI Contrast Agents II: Macrocyclic Ligands. (V. Jacques and J. Desreux). Protein--Bound Metal Chelates (S. Aime, et al.). Stability and Toxicity of Contrast Agents (E. Brucher and A. Sherry). Computational Studies Related to Gd(III)--Based Contrast Agents (D. Sulzle, et al.). Structure and Dynamics of Gadolinium--Based Contrast Agents (J. Peters, et al). Multi--Frequency and High--Frequency EPR Methods in Contrast Agent Research: Examples from GdA+ Chelates (R. Clarkson, et al). Particulate Magnetic Contrast Agents (R. Muller, et al). Photophysical Aspects of Lanthanide(III) Complexes (J. Bruce, et al).

968 citations


Journal ArticleDOI
TL;DR: As the first gadolinium-based blood pool agent in human trials, MS-325 has the potential to enhance both dynamic and steady-state MR angiograms and provides vascular signal enhancement superior to that provided with other agents.
Abstract: PURPOSE: To evaluate the protein-binding and signal enhancement characteristics of MS-325, a gadolinium-based magnetic resonance (MR) imaging blood pool agent that binds to albumin, and compare results with those obtained with existing gadolinium- and iron oxide-based agents. MATERIALS AND METHODS: Protein binding in human plasma was measured by means of ultrafiltration. T1 relaxation times (20 MHz) were measured in human plasma or ex vivo samples from rabbits and monkeys injected with 0.1 mmol of MS-325 per kilogram of body weight. Imaging (three-dimensional fast imaging with steady-state precession, or FISP) was performed at 1.0 T in phantoms, which contained varying concentrations of different agents, or rabbits after injection of 0.015-0.100 mmol/kg MS-325. RESULTS: MS-325 is 80%-96% bound in human plasma and exhibits a relaxivity approximately six to 10 times that of gadolinium diethylenetriaminepentaacetic acid (DTPA). Images of phantoms containing MS-325 were significantly brighter than those conta...

444 citations



Frequently Asked Questions (1)
Q1. What contributions have the authors mentioned in the paper "Sm and in dtpa derivatives with high hepatic specificity: in vivo and in vitro studies" ?

Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp ( L ) and the ligand DTPA ( BOM ) 1 3 153 31 111 31 ( BOM5benzyloxymethyl ) ( L ), radiolabelled with Sm and In, were studied as potential hepatospecific gamma scintigraphic 2 agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The La 31 1 and In chelates of L and L show some structural and dynamic differences in aqueous solution, as studied by H NMR spectroscopy.