Chemistry Reference
In-Depth Information
accuracy and effectiveness [3]. studies comparing the accuracy of dosimetry performed with
86
Y/
111
In-dOTA-TOC and
111
In-dTPA-octreotide as surrogates for
90
Y-dOTA-TOC therapy revealed that
111
In-dTPA-octreotide and
111
In-dOTA-TOC
had significantly different organ uptake when compared to the analogous
86/90
Y complexes [67, 69]. The chemically identical
option
86
Y-dOTA-TOC was the most suitable, with
86
Y being an ideal surrogate for
90
Y [67, 69]. One minor shortcoming of
86
Y is that the half-life of 14.7 hours, although long enough for most applications, does not enable image acquisition beyond
48-72 hours (unlike
111
In, t
1/2
= 67.9 h). Another potential problem with
86
Y is production and limited availability. PET imaging
is generally considered to be superior to sPECT; however, PET cameras are not as clinically ubiquitous as are sPECT cam-
eras. If equipment is available and half-lives are appropriately matched, PET imaging with isotopes such as
124
I,
68
Ga,
86
Y,
and
89
Zr would be preferred to sPECT imaging with isotopes such as
123/125
I or
111
In. The principle that differences in bioequiva-
lence are observed for chelators containing different radiometals and/or different chelate isomers is universally applicable to
all of the radiometals discussed in this section (
64
Cu/
68
Ga/
89
Zr).
5.4.3
stability of
86
yttrium-Based radiopharmaceuticals
The metal ions Ga(III) and Fe(III) are bound with very high affinity by the blood serum protein transferrin; however, larger
cationic metal ions such as Y(III) and the lanthanides are not bound as strongly [18, 38, 70-74]. The larger lanthanides such
as neodymium and praseodymium are bound even more poorly and are often not able to occupy both binding sites of trans-
ferrin [71]. The metal ions yttrium(III), lutetium(III), and gadolinium(III) have all been shown to bind to transferrin,
although not as strongly as do iron(III), gallium(III), and to a lesser extent indium(III) [18, 38, 70-74]. One explanation for
the weaker binding of the lanthanides to transferrin is based on their large size being a poor fit into the binding sites, with
the smaller charge-to-radius ratio and use of 4f orbitals (weaker interaction than 3d orbitals of iron) decreasing binding
affinity [71]. Following this, it has been suggested that the main reason for the poor binding of large metal ions to transferrin
is strictly a result of steric repulsion of the more crowded
C
-terminus binding site [72]. A convincing argument has also been
made that transferrin binding strength is better related to metal ion acidity than size [75-77]. This has been demonstrated
with the large but very acidic metal ion bismuth(III), which has an abnormally high binding affinity for transferrin despite
its size (103 pm, log
K
1
= 19.4, and log
K
2
= 18.5) [75-77]. Both arguments support the prediction of a low binding affinity
of Y(III) for transferrin.
The transferrin stability constants for binding one or two lu(III) ions have been determined to be log
K
1
* = 11.08 and
log
K
2
* = 7.93, which can be seen to be many orders of magnitude smaller than the binding affinity for Ga(III) and Fe(III)
[72]. The transferrin stability constant for the rare earth metal ion Y(III) has not been reported to our knowledge; however,
based on the arguments above, it can be reasonably estimated to be low, similar to that for lutetium. In light of the moderate
stability binding of the lanthanides to transferrin, the stability of Y(III) and lanthanide complexes would be best evaluated
by blood serum incubation or
in vivo
biodistribution studies, so that complexes would be challenged by a broad spectrum
of endogenous
in vivo
competition. Yttrium and the lanthanides have especially high uptake in bone, and free
90
Y injected
into a human is 50% associated with bone, with the next highest organ uptake being 25% in the liver [78]. There is also
evidence that intact cationic lanthanide complexes can adsorb onto the surface of bone, demonstrating that even chelate-
bound radiometals may accumulate in bone under certain circumstances [79]. In light of the high affinity of Y(III)
complexes for bone, stability assays should be performed that take this into consideration (e.g., biodistribution, hydroxy-
apatite competition).
5.4.4
86
yttrium radiometallation protocols
Y(III) is a very hard metal ion, and due to its lower acidity (pKa = 7.7), it is less prone than Zr(IV), Ga(III), and In(III) to
forming insoluble hydroxides at neutral ph. General radiometallation protocol follows that once a solution of
86
Y is pro-
cured (usually as an acidic solution in 0.1 M hCl or nitric acid), the desired quantity of activity is transferred to a buffered
solution containing a chelator or a BFC-biovector conjugate, allowed to incubate until quantitatively radiometallated, and
finally purified before administration [3, 42, 66, 80-82]. Acyclic chelators such as ChX-A″-dTPA are typically incubated
for 20-60 minutes at room temperature, but are sometimes heated to improve labelling efficiency with certain biovectors.
Macrocyclic chelators such as dOTA typically require temperatures in the range of 70-100 °C for 15-60 minutes.
90
Y
labelling techniques are identical to those for
86
Y, with the exception that the high-energy β
-
emissions of
90
Y can cause a
higher degree of biomolecule radiolysis (bond cleavage leading to decomposition), depending on the amount of activity and
the dilution and buffer used [83]. Another consideration is that the specific activity and concentration of radiometals may
vary between different isotopes, because they are often made through different production routes. A majority of the con-
cepts in radiometal BFC design that have been discussed for Y(III) are applicable to the other radiometals discussed in this
chapter (
68
Ga/
64
Cu/
89
Zr).
