Sc-HOPO: A Potential Construct for Use in Radioscandium-Based Radiopharmaceuticals.

Three isotopes of scandium─43Sc, 44Sc, and 47Sc─have 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.

Current State of 44Ti/44Sc Radionuclide Generator Systems and Separation Chemistry.

In recent years, there has been an increased interest in 44Ti/44Sc generators as an onsite source of 44Sc for medical applications without needing a proximal cyclotron. The relatively short half-life (3.97 hours) and high positron branching ratio (94.3%) of 44Sc make it a viable candidate for positron emission tomography (PET) imaging. This review discusses current 44Ti/44Sc generator designs, focusing on their chemistry, drawbacks, post-elution processing, and relevant preclinical studies of the 44Sc for potential PET radiopharmaceuticals.

Current State of Targeted Radiometal-Based Constructs for the Detection and Treatment of Disease in the Brain.

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.

Improved synthesis of the bifunctional chelator p-SCN-Bn-HOPO.

The bifunctional ligand p-SCN-Bn-HOPO, which has four 1,2-hydroxypyridinone groups on a spermine backbone with an isothiocyanate linker, has been shown to be an efficient and stable chelator for Zr(iv) and, more importantly, the radioisotope 89Zr for use in radiolabeling antibodies for positron emission tomography (PET) imaging. Previous studies of 89Zr-HOPO-trastuzumab in mice showed low background, good tumor to organ contrast, and very low bone uptake which show p-SCN-Bn-HOPO to be an important next-generation bifunctional chelator for radioimmunoPET imaging with 89Zr. However, the reported synthesis of p-SCN-Bn-HOPO involves nine steps and multiple HPLC purifications with an overall yield of about 1.4%. Herein we report an improved and efficient synthesis of p-SCN-Bn-HOPO in four steps with 14.3% overall yield which will improve its availability for further biological studies and wider application in PET imaging. The new synthetic route also allows variation in linker length and chemistries which may be helpful in modifying in vivo clearance behaviors of future agents.

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for (89)Zr ImmunoPET.

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 (89)Zr(4+) cation is being released in vivo. Therefore, a more robust chelator for (89)Zr 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 (89)Zr(4+) 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 (89)Zr. 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 (89)Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for (89)Zr-DFO-trastuzumab while (89)Zr-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 (89)Zr. In vivo studies demonstrate the successful use of (89)Zr-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 (89)Zr-HOPO-trastuzumab suggests superior stability of the (89)Zr-HOPO complex.

Alternative chelator for 89Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO).

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 (89)Zr(4+); however, accumulation of (89)Zr in the bones of mice suggests that (89)Zr(4+) is released from DFO in vivo. An improved chelator for (89)Zr(4+) could eliminate the release of osteophilic (89)Zr(4+) 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 (89)Zr-HOPO matched or surpassed that of (89)Zr-DFO in every experiment. In healthy mice, (89)Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for (89)Zr-based PET imaging agents.

PET imaging with 89Zr: from radiochemistry to the clinic.

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 (99m)Tc; 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.