Chemistry Reference
In-Depth Information
taBle 5.2 relevant properties of metal cations:
a
Ionic radius in
picometers [15], cn = coordination number,
b,c
in water as hydrated
Ions [16, 17].
Metal
Ionic Radius
a
(Cn)
p
K
a
b
k
exchange
(Water)
c
, s
-1
Cu(II)
57 (4)
7.53
2 × 10
8
65 (5)
73 (6)
Ga(III)
62 (6)
2.6
7.6 × 10
2
Y(III)
102 (8)
7.7
1.3 × 10
7
108 (9)
Zr(IV)
72 (6)
0.22
-
84 (8)
89 (9)
of a metal ion can drastically change its coordination properties with a chelator, as evidenced by the activity of bacterial iron
binding siderophores such as enterobactin and desferal [14]. Bacteria excrete siderophores to bind iron(III) from the sur-
rounding environment with exceptionally high binding affinity and then release the metal when inside the bacteria via
reduction to iron(II) [14]. Copper is known to be redox active and has potential to be reduced and subsequently decomplexed
in vivo
. As described by the hard-soft acid-base theory (hsAB), copper(II) is a borderline soft metal ion, whereas gallium(III),
yttrium(III), and particularly zirconium(IV) are very hard acidic metal ions and prone to hydrolysis and hydroxide formation
(Table 5.2).
under less acidic conditions the metal ions Ga(III) and Zr(IV) will readily form insoluble hydroxide species that do not
coordinate with chelators. When these acidic metal ions are complexed by strong chelators, the formation of hydroxides is
retarded and complexes can remain stable over a wide ph range (some even in 3-6 M hCl). Cu(II) complexes are often
unstable with respect to metal ion decomplexation, because Cu(II) has a d
9
electronic configuration and is prone to distortions
(e.g., axial Jahn-Teller distortions in six coordinate octahedral complexes). Cu(II) has a very high water exchange rate of
2 x 10
8
s
-1
(Table 5.2) and shows a high degree of lability [15-17]. These inherent electronic instabilities toward redox
chemistry and geometric distortions in Cu(II) complexes require caution and extra vigilance in chelator selection. If a
chelator-metal ion complex can be crystallised, its solid-state structure can be obtained by X-ray crystallography in order to
study its geometry and bonding. solid-state structures provide important information on the coordination number, geometry,
and specific donor atoms used in a complex; however, the solid-state structure is often not representative of the solution-
phase behaviour of a complex [18, 19].
5.2
radIopharmaceutIcal desIgn
The modular design of BFC systems allows for a theoretically limitless number of biovectors (peptides, nucleotides, anti-
bodies, nanoparticles, etc.) to be conjugated, providing site-specific molecular targeting to a constantly expanding number
of disease states and biochemical processes. The radiometal-chelate complex has a large impact on the pharmacokinetics of
the BFC-biovector conjugate, with many radiometal complexes being very hydrophilic and providing rapid renal excretion
[1-6]. BFCs have an attractive level of modularity built into their design, because they contain several core modules that can
be swapped (with varying degrees of difficulty) to provide vastly different applications, yielding a rich set of tools for
nuclear medicine practitioners. These modules are discussed as: (1) the
radiometal
, which can be changed to tune the radi-
ation type (γ for sPECT, β
+
for PET, and β
-
, α, or Auger electrons for therapy); (2) the
chelator
, which can be picked to
optimise binding and stability with a chosen radiometal; (3) the
bioconjugation sit
e, which can be changed to various func-
tionalisable handles for different types of linkages, including spacer groups that can be added to ensure minimal impact on
receptor targeting (often short polymers or peptides); and (4) the
biovectors
, which can be chosen as molecular targeting
groups for nearly any biochemical process or tissue type (Figure 5.1). As an example of BFC modularity, theranostics are
radiopharmaceutical agents that share the same molecular scaffold (same chelator and biovector), but provide diagnostic
information when using an appropriate sPECT/PET isotope such as
68
Ga/
111
In/
89
Zr/
86
Y and provide a therapeutic effect when
using β
-
emitters such as
90
Y/
177
lu [20].
Although each radiometal has different preferences for ligand donor atoms (n, O, s), coordination number, and complex
geometry, there are many key design considerations that can be applied universally [21]. ligand synthesis should be
relatively simple and avoid stereoisomers and non-enantio/diastereospecific reactions, because different isomers can often
