Chemistry Reference
In-Depth Information
5.7.2
recent
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Zirconium work
This emerging PET imaging nuclide is currently underutilised, and its use may be expanded through development of new
chelators to provide more effective coordination, solubility, and bioconjugation chemistry. Although
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Y is an ideal surrogate
nuclide for use with
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Y as a theranostic pair (they are chemically identical),
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Zr may be a more suitable imaging surrogate
for other radiometals or for imaging/dosimetry applications that require data collection beyond 72 hours. The higher charge
of 4+ makes
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Zr more challenging to incorporate into BFC systems while still retaining bioequivalence with other common
3+ cationic metal ions (In(III), Ga(III), Y(III), lu(III)), because the overall chelate-complex charge is different. dFO has
been functionalised with various bioconjugation handles (Figure 5.14), such as isothiocyanates [165], alkyl halides [155],
and succinimidyl esters (nhs ester) [166].
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Zr has an ideal half-life for use with antibody biovectors, and
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Zr-dFO has been conjugated with the antibody J591,
which targets prostate-specific membrane antigen (PsMA) expression and has been used for imaging prostate cancer [158].
Another example is the antibody conjugate
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Zr-dFO-TRC105, which has been used for targeting Cd105 expression (marker
for tumour angiogenesis) [167]. Toward understanding the metabolism of simple
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Zr complexes, recent work has demon-
strated that
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Zr-chloride accumulates in the liver with little secretion, and
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Zr-oxalate accumulates mostly in bone and joints
[78, 158]. This example illustrates the strong effect that the specific coordination species of the metal ion has on the biodis-
tribution of the radiometal. In contrast to the chloride and oxalate species, non-conjugated 'bare'
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Zr-dFO is observed to
clear very rapidly through the kidneys with minimal nonspecific organ uptake [158]. This demonstrates a biological “clean
slate” for radiopharmaceuticals based on the
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Zr-dFO complex, which is a good starting point in chelator development and
selection.
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Zr that is lost from a BFC
in vivo
typically localises in bone, as demonstrated by dOTA- and dTPA-based
antibody conjugates with cetuximab that show
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Zr accretion in the thighbone 72 hours post injection due to
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Zr-decomplexation
[168]. studies with Bi(III) have suggested that transferrin binding is strongly correlated to metal ion acidity, regardless of
metal ion size, which suggests the very acidic Zr(IV) (pKa = 0.22) may bind strongly [75-77]. It has also been reported that
Zr(IV) binds transferrin in an unnatural fashion, resulting in a different coordination environment than for other metal ions,
which affects transferrin receptor binding and results in different biological behaviour and biodistribution [169]. Considering
this, transferrin may potentially be strong competition for Zr(IV) binding
in vivo
, but once bound it will not have the same
biodistribution pattern as other radiometal ions such as
68
Ga and
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In [169].
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Y-Zevalin and
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Zr-Zevalin have demonstrated
very similar biodistribution profiles, except that
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Zr-Zevalin showed significantly higher bone and liver uptake after 72
hours, suggesting
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Zr-decomplexation [161]. Compromised physiological stability of
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Zr with dTPA- and dOTA-based
BFCs, as demonstrated by
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Zr-Zevalin (based on the modified dTPA chelator tiuxetan) [161], is the main reason why dFO
is most commonly chosen for BFC applications. The rapid low-temperature radiometallation kinetics of dFO is amenable
toward antibody biovectors, and the long half-life of
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Zr is well matched with the long biological half-lives of antibodies.
5.7.3
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Zirconium radiometallation protocols
A summary of radiolabelling protocols for
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Zr is concise, because it is essentially restricted to dFO-based BFCs [170]. In
one unique example, a
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Zr-dFO-mouse serum albumin (mAlb) conjugate has been synthesised that uses the enhanced per-
meability and retention effect (EPR effect) and shows similar non-selective retention across various tumour phenotypes
[171]. The EPR effect relies on large particles becoming trapped and retained in 'leaky' tissue that has abnormal vascular
permeability, which is a hallmark of tumours and sites of inflammation and is exploited by many nanoparticle and micro-
sphere technologies [172]. Pre-coordinating dFO with Fe(III) is a common technique that serves to protect the hydroxamate
groups and modulate solubility [173, 174]. The Fe(III) bound to dFO is removed prior to
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Zr-labelling with an EdTA or
dTPA solution, purified by size-exclusion chromatography (Pd-10 or hPlC), and then radiometallated with
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Zr (typically
from
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Zr in oxalic acid) for ~60 minutes at ambient temperature [155, 161, 165, 174, 175]. More recently with the commercial
availability of p-sCn-Bn-dFO, the Fe(III) protection is not utilised, and immunoconjugates that incorporate p-sCn-Bn-
dFO can be directly radiolabelled.
5.7.4
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Zirconium summary
This radiometal has seen a significant rise in attention over the last five years, and
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Zr-based radiopharmaceuticals have shown
great promise for use with antibody biovectors due to their close match in radioactive and biological half-lives.
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Zr is the longest
half-life PET imaging radiometal (78.5 hours) discussed in this chapter and therefore is ideal for collecting imaging and dosim-
etry data at time points of 3 to 7 days post injection.
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Zr is ideal in its nuclear decay properties as a PET alternative to
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In for
use as a matched isotope pair with theranostic radiopharmaceuticals that incorporate long-lived isotopes such as
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Y and
177
lu.
The long half-life and high-energy γ emissions of
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Zr can result in patients acquiring significant absorbed doses; however, the
