Chemistry Reference
In-Depth Information
taBLe 8.1
rate constants for gadolinium exchange in a range of complexes.
Complex
k
ind
/s
−1
k
dep
/ M
-1
s
-1
k
obs
(pH = 1)
k
obs
(pH = 7.4)
ref
[gd.dOTA]
-
<5 × 10
-8
5 × 10
-6
3-5 × 10
-7
<5 × 10
-8
[36, 97]
gd.HP-dO3A
-7(±20) × 10
-10
2.6 × 10
-4
2.6 × 10
-5
< 1.3 × 10
-9
[36]
gd.dO3A-butrol
2 × 10
-10
2.8 × 10
-5
2.8 × 10
-6
2 × 10
-10
[36]
gd.dTPA-BMA
-
-
>2 × 10
-2
?
[6]
gd.dO3A
-
-
2.3 × 10
-3
?
[5]
[gd.dTPA]
2-
-
-
1.2 × 10
-3
?
[6]
For all clinically approved complexes, slow exchange of gadolinium is observed at physiological pH (where the pH
independent term is likely to dominate). Because it is desirable that complexes be kinetically stable, it will come as no
surprise that studies on the most effective complexes can be time-consuming. Many authors have aimed to speed up the
process by measuring
k
exch
at low pH, where (again unsurprisingly) the pH dependent term is dominant [5, 6].
Release of metal ions from polydentate ligands requires some displacement of ligand donor atoms from the metal
coordination sphere. This can either occur spontaneously or through protonation of a donor atom (giving rise to the pH-
dependent component). Studies on dTPA-bisamide derivatives show multiple diastereoisomers that interconvert through
dissociation of up to three ligand donor atoms from the metal centre [38, 39]. Such an extreme process is not observed in
dTPA itself, as a result of the improved donor ability of the extra carboxylate donors in dTPA. It also goes a long way to
explaining how dTPA-bisamides are relatively unstable. In normal circumstances, this may appear an academic consideration.
However, renally compromised patients have exhibited a debilitating disorder known as nephrogenic systemic fibrosis (NSF)
following contrast imaging [40, 41]. This has been found to correlate very strongly with the use of bisamide dTPA deriva-
tives and gadolinium dissociation from the chelate, suggesting that kinetic stability is of great importance when considering
suitable contrast agents. This is one area in which there is likely to be a need for more data to be obtained: The majority of
kinetic measurements have been made at low pH. However, study of equation 8.9 and the rate constants in Table 8.1 clearly
reveal that, for all the complexes where data on both
k
ind
and
k
dep
have been obtained, the pH independent pathway for com-
plex dissociation will be almost completely dominant in the pH range available to viable organisms. For the pH dependent
pathway to be important at physiological pH,
k
dep
must be very much greater than
k
ind
. In the absence of a more complete
body of data, it would be unwise to draw more detailed conclusions at this time. However, even with the data available in the
table, it is clear that the pH dependent pathway will only dominate for dOTA when the pH is less than 2, while in the case
of HP-dO3A and gadobutrol, pH-mediated lanthanide release will become important at pHs as high as 6. Thus it is clear that
structure and ligand pK
a
will play a key role.
8.4
ratIonaLIsIng the BehavIour of mrI contrast agents
Relaxivity is a useful measure of the effectiveness of a complex as a contrast agent; the best contrast agents will have large
relaxivities per mmol of gadolinium, effectively meaning that good images can be obtained with lower concentrations of
contrast agent. The relaxivity r
i
is defined by the observed concentration dependence of (1/
T
i
)
obs
according to the equation
(/ )
1
T
=
(
1
/
T
)
+
i
rgd
[]
i
=
12
,
(8.10)
i
obs
dia
As such, the relaxivity is readily determined from a number of
T
i
measurements over a range of contrast agent concentrations
as the slope of a plot of 1/
T
i
against concentration of gadolinium. It is worth noting that the relaxivity itself will have units
of mmol(gd)
-1
s
-1
. In the later part of this chapter, where we address multimetallic complexes, it should be remembered that
r
i
is established per unit of gadolinium, rather than per unit of complex.
1
In a paramagnetic system,
T
1
and
T
2
are both influ-
enced by both diamagnetic and paramagnetic contributions. In general,
(/ )
1
T
=
(
1
/
T
)
+
(
1
/
T
)
i
=
1 2
,
(8.11)
i
obs
i
dia
i
para
where (1/
T
i
)
obs
is the reciprocal of the observed
T
i
, and (1/
T
i
)
dia
and (1/
T
i
)
para
are the reciprocals of the diamagnetic and para-
magnetic contributions respectively.
1
In other words, the effectiveness of a multimetallic complex might be thought of as being given by r
i
. n where n is the number of gadolinium ions in the
system.
