The advent of antibody-based cancer therapeutics has led to the concomitant rise in the development of companion diagnostics for these therapies, particularly nuclear imaging agents. A number of radioisotopes have been employed for antibody-based PET and SPECT imaging, notably 64Cu, 124I, 111In, and 99mTc; in recent years, however, the field has increasingly focused on 89Zr, a radiometal with near ideal physical and chemical properties for immunoPET imaging. In the review at hand, we seek to provide a comprehensive portrait of the current state of 89Zr radiochemical and imaging research, including work into the production and purification of the isotope, the synthesis of new chelators, the development of new bioconjugation strategies, the creation of novel 89Zr-based agents for preclinical imaging studies, and the translation of 89Zr-labeled radiopharmaceuticals to the clinic. Particular attention will also be dedicated to emerging trends in the field, 89Zr-based imaging applications using vectors other than antibodies, the comparative advantages and limitations of 89Zr-based imaging compared to that with other isotopes, and areas that would benefit from more extensive investigation. At bottom, it is hoped that this review will provide both the experienced investigator and new scientist with a full and critical overview of this exciting and fast-developing field.
Zirconium-89 is an effective radionuclide
for antibody-based positron
emission tomography (PET) imaging because its physical half-life (78.41
h) matches the biological half-life of IgG antibodies. Desferrioxamine
(DFO) is currently the preferred chelator for 89Zr4+; however, accumulation of 89Zr in the bones of
mice suggests that 89Zr4+ is released from DFO
in vivo. An improved chelator for 89Zr4+ could eliminate the release of osteophilic 89Zr4+ and lead to a safer PET tracer with reduced
background radiation dose. Herein, we present an octadentate chelator
3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative
to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated
experimentally and theoretically. The stability of 89Zr-HOPO
matched or surpassed that of 89Zr-DFO in every experiment.
In healthy mice, 89Zr-HOPO cleared the body rapidly with
no signs of demetalation. Ultimately, HOPO has the potential to replace
DFO as the chelator of choice for 89Zr-based PET imaging
agents.
Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the 89Zr4+ cation is being released in vivo. Therefore, a more robust chelator for 89Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of 89Zr4+ and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with 89Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the 89Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for 89Zr-DFO-trastuzumab while 89Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for 89Zr. In vivo studies demonstrate the successful use of 89Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with 89Zr-HOPO-trastuzumab suggests superior stability of the 89Zr-HOPO complex.
Three isotopes of scandium43Sc, 44Sc, and 47Schave attracted increasing
attention
as potential candidates for use in imaging and therapy, respectively,
as well as for possible theranostic use as an elementally matched
pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO)
(or HOPO), an effective chelator for hard cations, as a potential
ligand for use in radioscandium constructs with simple radiolabeling
under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully
characterized, both experimentally and theoretically. [47Sc]Sc-HOPO exhibited good stability in chemical and biological challenges
over 7 days. In healthy mice, [43,47Sc]Sc-HOPO cleared
the body rapidly with no signs of demetalation. HOPO is a strong candidate
for use in radioscandium-based radiopharmaceuticals.
The
continual development of radiopharmaceutical agents for the
field of nuclear medicine is integral to promoting the necessity of
personalized medicine. One way to greatly expand the selection of
radiopharmaceuticals available is to broaden the range of radionuclides
employed in such agents. Widening the scope of development to include
radiometals with their variety of physical decay characteristics and
chemical properties opens up a myriad of possibilities for new actively
targeted molecules and bioconjugates. This is especially true to further
advance the imaging and treatment of disease in the brain. Over the
past few decades, imaging of disease in the brain has heavily relied
on agents which exploit metabolic uptake. However, through utilizing
the broad range of physical characteristics that radiometals offer,
the ability to target other processes has become more available. The
varied chemistries of radiometals also allows for them to incorporated
into specifically designed diverse constructs. A major limitation
to efficient treatment of disease in the brain is the ability for
relevant agents to penetrate the blood-brain barrier. Thus, along
with efficient disease targeting, there must be intentional thought
put into overcoming this challenge. Here, we review the current field
of radiometal-based agents aimed at either imaging or therapy of brain
disease that have been evaluated through at least in vivo studies.
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