UniLaSalle.

AGHYLE research group.

Environmental engineer.
Sixth Semester.
Summer Research.

Extrapolation of the Mg-DTPA-BMA constants, by linear

regression.

Professor:
Dr. Olivier Pourret.

International Student.

Student:
Landaverde Sandoval Daniel.

Delivery Date of the Work Work : 27 of July of 2018.

Introduction.
Nowadays, interest about Gadolinium gadolinium (Gd) chelates has increase, this is
because this chelates are usually used as contrast agents for magnetic resonance
imaging (MRI) (12). Normally the Gadolinium Gd complex are stable, or at least stable
enough to been excreted from the human body, before the complex dissociates (2). But
However, sometimes the problem of dissociation is not only generated in the human
body, it also can also occurs once this complex has been excreted from the body. It
results in a , and now the risk of dissociation can happen in the environment (16).
The problem of the dissociation of the gadolinium Gd complex dissociation is that when
it is in ionic form, both the ligand and Gadolinium Gd are toxic to humans and can lead
to several health problems. That is why, at present, these complexes are studied, in
order to know the reasons why they are dissociated and to know, which of the
complexes is more stable to use it in MRI. The next equation presents the kinetic
stability of this process (17) (6).
[ 1]
GdL ⇆ Gd 3+¿+ L¿
In the last equation [1], GdL represents the complex between Gadolinium Gd and the
ligand, and after the arrowson the right of the reaction, the complex ions once
dissociated are presented (L, Gd3+), and as mentioned, the problem of these ions is that
they can become very toxic (6).
It is worth mentioning that one of the reasons why these complexes are dissociated is
due to the presence of other free ions in the medium, which propitiate or accelerate that
these complexes break the bond between them, this phenomenon is call
transmetallation, and is represented by thein next equation [2] (6).
[ ]n−1 ¿
2+¿ ⇆Gd 3+ ¿+ ML
GdL n+ [ M ]
¿
[ 2]
The transmetallation occurs in the body thanks to the large number of ligands and
metals that human fluids presents (ex.e.g. blood), also this process could occurs in the
environment, specifically in the water, this thanks to the presence of free ions (Ca 2+,
Mg2+, Zn2+, K+2, etc…) that could displace de Gd+3+ from its complex (6).
However, there is a way that can prevent the Gadolinium Gd complex from dissociating,
or at least dissociate as little as possible, this is achieved by adding a salt of the ligand
that is linked with GadoliniumGd, thisand this process is seen to work specifically with
the complex Gd-DTPA-BMA (2).
In the report we will focus especially on two Gadolinium Gd complex, DTPA-BMA and
DOTA, also we will do a comparison between this to complex and try to make an
extrapolation of one of them to get a constant value that we do not have. In the Ttable 1,
we compare the physicochemical and thermodynamic characteristics of Gd-DOTA, and
Gd-DTPA-BMA.
Table 1 Comparisons between Gd-DOTA and Gd-DTPA-BMA (physical-chemical and
thermodynamic characteristics

Table 1. Comparisons between Gd-DOTA and Gd-DTPA-BMA

(physical-chemical and thermodynamic characteristics
Complex.
Gd-DOTA Gd-DTPA-BMA

 Macrocyclic.  Open Chain.

 Ionic.  Nonionic.
 Strong Bound.  Weak Bound.
 Lower amount of residual Gd in  Higher amount of residual Gd in
the body. the body.
 Less basic.  More basic.
 Kinect stability is higher.  Kinect stability is lower.
 No Free ligand added.  Has a ligand (Formulation).
 Dissociation half-lives are  Dissociation half-lives are shorter.
markedly longer.  Lower thermodynamic constant (
 Higher thermodynamic constant ( log K yherm ).
log K yherm ).  The complex is more instable
 The complex is more stable than than the radicals are.
the radicals are.  This complex has less of the five-
 This complex has more of the membered rings (six).
five-membered rings (eight).

Results.
In this report, we present the values of certain constants of the complexes of some
3+¿ ¿
2+¿ ,Gd ¿
2+¿ ,Cu2+¿ , Mg
metals (Ca 2+¿ ,Zn ¿ and the ligands DOTA, DTPA-BMA and DTPA, these values
¿
¿

shown in the followingT tables 2, 3 and 4.:

Table 2 Comparisons of stability constants of Ca(II), Zn(II), Cu(II), Mg(II) and Gd(III)
with the ligand DOTA.
Table 2. Comparisons of stability constants of Ca(II), Zn(II), Cu(II), Mg(II) and Gd(III)
with the ligand DOTA.
Gadoliniu Value (in pH T Medium C
 m β=( X ) , K =(Y )¿ (°C) (mol L-1)
Sspecies
Gd- 24.03 (X) −¿ 25 Me4NCl 0.1
DOTA(9)
Gd- 24.70 (Y) −¿ −¿ NaCl 0.15
DOTA(16)
Gd- 25.60 (Y) 7.4 −¿ −¿ 0.5
DOTA(6)
Gd- 24.67 (X) −¿ 25 Me4NCl 0.1
DOTA(10)
Gd- 24.70 (X) −¿ 25 Me4NCl 0.1
DOTA(10)
Gd- 24.00 (X) −¿ 25 Me4NCl 0.1
DOTA(10)
Gd- 25.40 (X) −¿ 25 Me4NCl 0.1
DOTA(10)
Gd- 27.00 (X) −¿ 25 NMe4NO3 0.1
DOTA(10)
Gd- 25.30 (X) −¿ 25 NaCl 0.1
DOTA(10)
Gd- 25.10 (X) −¿ 25 NaCl 0.1
DOTA(10)
Gd- 26.03 (X) −¿ 25 KCl 0.1
DOTA(10)
Gd- 25.58 −¿ 25 Me4NCl 0.1
DOTA(10)
Gd- 24.99 −¿ 25 Me4NCl 0.1
DOTA(10)
Gd- 25.00 (Y) −¿ 25 −¿ −¿
DOTA(4)
Ca- 17.50 −¿ −¿ −¿ −¿
DOTA(3)
Ca- 17.23 −¿ −¿ −¿
DOTA(12)
Ca- 16.37 −¿ 25 KCl 1
DOTA(11)
Ca- 17.23 −¿ 25 (CH3)4NN 0.1
DOTA(8) O3
Zn- 18.17 −¿ 25 KCl 1
DOTA(11)
Zn- 21.00 −¿ −¿ −¿ −¿
DOTA(3)
Zn- 21.05 −¿ −¿ −¿ −¿
DOTA(12)
 Zn- 21.05 −¿ 25 (CH3)4NN 0.1
DOTA(8) O3
Cu- 22.63 −¿ −¿ −¿ −¿
DOTA(12)
Cu- 22.00 −¿ 25 NaCl 0.15
DOTA(1)
Cu- 22.21 −¿ 25 NaCl 0.15
DOTA(1)
Cu- 22.72 −¿ 25 KCl 1
DOTA(11)
Cu- 22.21 −¿ 25 (CH3)4NN 0.1
DOTA(8) O3
Mg- 11.15 −¿ 25 KCl 1
DOTA(11)
Mg- 11.92 −¿ 25 (CH3)4NN 0.1
DOTA(8) O3

Table 3 Comparisons of stability constants of Ca(II), Zn(II), Cu(II), Mg(II) and Gd(III)
with the ligand DTPA-BMA.
Table 3. Comparisons of stability constants of Ca(II), Zn(II), Cu(II), Mg(II) and Gd(III)
with the ligand DTPA-BMA.
Gadolinium Sspecies Value pH T Medium C
Log K (°C) (mol L-1)
Gd-DTPA-BMA(6) 16.9 7.4 −¿ −¿ 0.5
Gd-DTPA-BMA(17) 16.85 −¿ 25 Me4NCl 0.1
Gd-DTPA-BMA(4) 16.6 −¿ −¿ −¿ −¿
Gd-DTPA-BMA(4) 16.8 −¿ −¿ −¿ −¿
Gd-DTPA-BMA(5) 16.85 7.4 25 KCl 0.1
Gd-DTPA-BMA(1) 16.64 −¿ 25 NaCl 0.15
Gd DTPA-BMA(1) 16.85 −¿ 25 NaCl 0.15
Ca-DTPA-BMA(5) 7.17 −¿ 25 NaCl 0.1
Ca-DTPA-BMA(11) 7.2 −¿ 25 NaCl 0.1
Zn-DTPA-BMA(5) 12.04 −¿ 25 NaCl 0.1
Zn-DTPA-BMA(1) 12.42 −¿ 25 NaCl 0.15
Cu-DTPA-BMA(5) 13.03 −¿ 25 NaCl 0.1
Cu-DTPA-BMA(1) 16.30 −¿ 25 NaCl 0.15
 Mg-DTPA-BMA Value −¿ −¿ −¿ −¿
extrapolated.

Table 4 Comparisons of stability constants of Ca(II), Zn(II), Cu(II), Mg(II) and Gd(III)
with the ligand DTPA.

Table 4. Comparisons of stability constants of Ca(II), Zn(II), Cu(II), Mg(II) and Gd(III)
with the ligand DTPA.
Element and ligand. Value pH T Medium C
Log K (°C) (mol L-1)
Ca-DTPA(16) 10.63 −¿ 20 NaClO4 0.1
Ca-DTPA(16) 10.89 ± 0.1 −¿ 20 NaClO4 0.1
Ca-DTPA(16) 10.74 −¿ 25 NaClO4 0.1
Ca-DTPA(16) 10.6 −¿ 25 NaClO4 0.1
Ca-DTPA(16) 10.58 −¿ −¿ NaClO4 0.1
Ca-DTPA(16) 9.82±0.008 −¿ 37 NaClO4 0.15
Ca-DTPA(16) 9.06± 0.03 −¿ 25 NaClO4 0.7
Ca-DPTA(3) 10.75 −¿ 25 NaCl 0.1
Ca-DPTA(2) 10.75 −¿ 25 NaCl 0.1
Zn-DTPA(12) 18.29 −¿ −¿ −¿ −¿
Zn-DTPA(5) 18.70 −¿ 25 NaCl 0.15
Zn-DTPA(1) 17.58 −¿ 25 NaCl 0.15
Cu-DTPA(1) 23.40 −¿ 25 NaCl 0.15
Cu-DTPA(2) 21.38 −¿ 25 NaCl 0.1
Cu-DTPA(12) 21.38 −¿ 25 NaCl 0.1
Cu-DTPA(1) 21.5 −¿ 25 NaCl 0.15
Cu-DTPA(7) 21.4+0.3 −¿ 25 (CH3)4NCl 0.1
Mg-DPTA(16) 9.03 −¿ 20 NaClO4 0.1
Mg-DPTA(16) 9.3 −¿ 25 NaClO4 0.1
Mg-DPTA(16) 8.56±0.016 −¿ 37 NaClO4 0.1
Mg-DPTA(16) 7.70±0.02 −¿ 25 NaClO4 0.1
Gd-DTPA(16) 22.46±0.07 −¿ 25 NaClO4 0.1
 Gd-DTPA(16) 22.46 −¿ 25 NaClO4 0.1
(16)
Gd-DTPA 20.73±0.06 −¿ 25 NaClO4 0.5
(16)
Gd-DTPA 20.68±0.07 −¿ 25 NaClO4 0.7
(16)
Gd-DTPA 21.15±0.02 −¿ 25 NaClO4 2

Also in this work are exposed certain constants values, which were used for the creation
of the graphs, and thanks to the graphs, linear regressions could be made, which allow
us to obtain a constant value for Mg-DTPA-BMA (Table 5). These values were selected
because the difference between them is very small, this obviously for each element in
independent
Table 5 Log K used in this study.

Table 5. values used to create the graphics

Metal Log K DOTA Log K DTPA-BMA Log K DTPA
Gd 24.03 16.85 22.48
Gd 24.7 16.85 22.46
Gd 24.67 16.6 20.73
Gd 24 16.8 20.68
Gd 25.6 16.85 21.15
Ca 17.5 7.17 10.58
Ca 17.23 7.2 10.6
Zn 21.05 12.04 18.58
Zn 21 12.42 18.7
Cu 22.63 13.03 21.5
Cu 22 16.3 21.38
a b
Mg 11.15 4.76 o -1.70 9.3
a
Dose values that were extrapolated from equation DTPA-BMA and DTPA.
b
Dose values that were extrapolated from equation DTPA-BMA and DOTA .

Graphics.
The following graphsFigures 1, 2 and 3 show a comparison between the complexes and
some metals, and the values of the constants in Table 5. the colors represent different
metals with their ligand (Gadolinium, Calcium, Zinc, copper and Magnesium).
 f(x) = 0
R² = 0 Comparison of DTPA-BMA and DOTA with diferents metals
27

25

23
Log K DOTA

21

19

17

15
6 8 10 12 14 16
Log K DTPA-BMA

Figure 1 Comparison of DTPA-BMA and DOTA log K with different metals. The colors
represent different metals with their ligand (Gadolinium, calcium, zinc, copper and
magnesium).

Comparison of DTPA-BMA and DTPA wiht diferents metals

24

22
f(x) = 1.07 x + 4.2
R² = 0.88
20

18
Log DTPA

16

14

12

10

8
6 8 10 12 14 16 18
Log DTPA-BMA.

Figure 2 Comparison of DTPA-BMA and DTPA log K with different metals. The colors
represent different metals with their ligand (Gadolinium, calcium, zinc, copper and
magnesium).
 Comparison of DTPA and DOTA with diferent metals
24

22 f(x) = 1.09 x − 5.12

R² = 0.84

20

18
Log K DTPA

16

14

12

10

8
10 12 14 16 18 20 22 24 26 28

Log K DOTA

Figure 3 Comparison of DTPA and DOTA log K with different metals. The colors
represent different metals with their ligand (Gadolinium, calcium, zinc, copper and
magnesium).

Statistic information.
The following table shows the values of the coefficients of determination (R 2), the
equations obtained in the linear regression, and also presents the value of the Mg-
DTPA-BMA constant obtained from the extrapolation, with the different Mg values.
-DOTA and Mg-DTPA.
Table 6 Equations and values obtained from the different linear regressions.
Table 6. Equations and values obtained from the different linear regressions.
Comparison Value of R2 Equation Value of Mg
between. (extrapolation)
DTPA and DTPA-BMA 0.8753 y=1.0691 x+ 4.2019 4.76
DOTA and DTPA-BMA 0.9118 y=0.7127 x +12.364 -1.70
DTPA and DOTA 0.8406 y=1.0939 x−5.1175 N/A

Chemical Structures.
Also in this bibliographic work, we present the chemical formula of Gd-DOTA and Gd-
DTPA-BMA, the synthesis of the complexes of Gd-DOTA and Gd-DTPA-BMA are
presented (Figures 4, 5, 6 and 7), also we expose the chemical equation of this
synthesis.

Scheme 1. Gd-DTPA-BMA (2D). Scheme 2. Gd-DTPA-BMA (3D).

N
HN NH
N N
Gd
O O

O O O O
H2O

Figure 4 2D scheme of Gd-DTPA-BMA. Figure 5 3D scheme of Gd-DTPA-BMA.

Scheme 3. Gd-DOTA- (2D). Scheme 4. Gd-DOTA (3D).

-*
OH2

O
O
O

N N O

Gd
O
N N

O
O
 Figure 6 2D scheme of Gd-DOTA- . Figure 7 3D scheme of Gd-DOTA.

Chemical equations and synthesis.

DOTA(10).
Part one:

OH2 +**
O O O
O
O H2O O
Gd + NH N OH
fast
HO
N NH OH2 NH N O
O Gd
O
O N
O NH
H2O
O

OH2 O
O

Part two:
+** OH2 +* +*
OH2 OH2
O (H)
O O H 2O O H2O O
O O O H2O O
H
OH2 NH N O Slow N N O Slow N N O
Gd Gd Gd
O O O
N NH N N N N
H 2O
O O H O
OH2 O OH2 O OH2 O
O O O
(H)
 + 2 H+
-
+2H
+ 2 OH- fast

OH2 -*

O O H2O O

N N O
Gd
O
N N
O
OH2 O
O

Part three:

OH2 -* -*
OH2
O O O
H2O O O O

+2H+ N N O
slow N N O
Gd Gd
O O
N N N N
O O
OH2 O O
O O

DTPA-BMA (15).
O O O O

+ NH4OH H2N C CH2 H +

CH2 C
C CH2 H CH2 C

O N H2C H2C N CH2 CH2 N

O
+ NH4OH
Gd+3 N H2C H2C N CH2 CH2 N + H2O

- - -
C CH2 CH2 C O CH2 C O C CH2 CH2 C O CH2 C O

O O O O O O

−¿ ¿
4−¿⇋ GdHL ¿

Equation of Gd+DOTA (Gd3 +¿+H L ¿

)

G d 3+¿+¿¿

PM=157.25 mol L-1 PM=400.388 mol L-1 PM= 557.638 mol L-1

3−¿⇋Gd H2 L ¿
Equation of Gd+DTPA+BMA (Gd 3 +¿+H 2 L ¿
)
 G d 3+¿+¿¿

PM=157.25 mol L-1 PM= 415.403 mol L-1 PM= 572.653 mol L-1
Conclusion.
We can see that the Gd-DOTA complex has a higher stability constant than Gd-DTPA-
BMA, this is because the first complex has micro-cycling ring that helps him to be more
stable, also the literature mention that the Gd-DOTA complex has a higher global
negative charge (6). This results in a stronger electrostatic metal-ligand interaction than
that in non-ionic chelates, like the DTPA-BMA (6).
Another point that make Gd-DTPA-BMA less stable is that this complex has non-ionic
donor atoms, these atoms are less basic and consequently more weakly bound to
gadolinium than ionic donor atoms (6).
In the work some estimations of the values of the constants of Mg-DTPA-BMA were
made, this by means of the use of the linear regression, the problem of this method, is
that the values obtained in the different cases, either for DTPA or DOTA, they were
completely different. This was because the values that are being sought are in the
insertion range of the linear regression, which does not allow us to affirm at one
hundred percent that our values are correct.
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