Lynn C. Francesconi

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.

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 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.

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

Europium(III) Reduction and Speciation within a Wells−Dawson Heteropolytungstate

The redox speciation of Eu(III) in the 1:1 stoichiometric complex with the alpha-1 isomer of the Wells-Dawson anion, [alpha-1-P 2W 17O 61] (10-), was studied by electrochemical techniques (cyclic voltammetry and bulk electrolysis), in situ XAFS (X-ray absorption fine structure) spectroelectrochemistry, NMR spectroscopy ( (31)P), and optical luminescence. Solutions of K 7[(H 2O) 4Eu(alpha-1-P 2W 17O 61)] in a 0.2 M Li 2SO 4 aqueous electrolyte (pH 3.0) show a pronounced concentration dependence to the voltammetric response. The fully oxidized anion and its reduced forms were probed by Eu L 3-edge XANES (X-ray absorption near edge structure) measurements in simultaneous combination with controlled potential electrolysis, demonstrating that Eu(III) in the original complex is reduced to Eu(II) in conjunction with the reduction of polyoxometalate (POM) ligand. After exhaustive reduction, the heteropoly blue species with Eu(II) is unstable with respect to cluster isomerization, fragmentation, and recombination to form three other Eu-POMs as well as the parent Wells-Dawson anion, alpha-[P 2W 18O 62] (6-). EXAFS data obtained for the reduced, metastable Eu(II)-POM before the onset of Eu(II) autoxidation provides an average Eu-O bond length of 2.55(4) A, which is 0.17 A longer than that for the oxidized anion, and consistent with the 0.184 A difference between the Eu(II) and Eu(III) ionic radii. The reduction of Eu(III) is unusual among POM complexes with Lindqvist and alpha-2 isomers of Wells-Dawson anions, that is, [Eu(W 5O 18) 2] (9-) and [Eu(alpha-2-As 2W 17O 61) 2] (17-), but not to the Preyssler complex anion, [EuP 5W 30O 110] (12-), and fundamental studies of materials based on coupling Eu and POM redox properties are still needed to address new avenues of research in europium hydrometallurgy, separations, and catalysis sciences.

166Ho and 90Y labeled 6D2 monoclonal antibody for targeted radiotherapy of melanoma: comparison with 188Re radiolabel.

INTRODUCTION An approach to radioimmunotherapy (RIT) of metastatic melanoma is the targeting of melanin pigment with monoclonal antibodies (mAbs) to melanin radiolabeled with therapeutic radionuclides. The proof of principle experiments were performed using a melanin-binding antibody 6D2 of IgM isotype radiolabeled with a β emitter (188)Re and demonstrated the inhibition of tumor growth. In this study we investigated the efficacy of 6D2 antibody radiolabeled with two other longer lived β emitters (90)Y and (166)Ho in treatment of experimental melanoma, with the objective to find a possible correlation between the efficacy and half-life of the radioisotopes which possess high energy β (E(max)>1.5 MeV) emission properties. METHODS 6D2 was radiolabeled with longer lived β emitters (90)Y and (166)Ho in treatment of experimental melanoma in A2058 melanoma tumor-bearing nude mice. The immunoreactivity of the radiolabeled 6D2 mAb, its in vitro binding to the MNT1 human melanoma cells, the biodistribution and therapy in A2058 human melanoma bearing nude mice as well as dosimetry calculations were performed. RESULTS When labeled with the longer lived (90)Y radionuclide, the 6D2 mAb did not produce any therapeutic effect in tumor bearing mice while the reduction of the tumor growth by (166)Ho-6D2 was very similar to the previously reported therapy results for (188)Re-6D2. In addition, (166)Ho-labeled mAb produced the therapeutic effect on the tumor without any toxic effects while the administration of the (90)Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. CONCLUSIONS (166)Ho-labeled mAb to melanin produced some therapeutic effect on the tumor without any toxic effects while the administration of the (90)Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. We concluded that the serum half-life of the 6D2 carrier antibody matched well the physical half-life of (166)Ho to deliver the tumoricidal absorbed dose to the tumor. Further investigation of this radionuclide for RIT of melanoma is warranted.

Self-standing, metal nanoparticle embedded transparent films from multi-armed cardanol conjugates through in situ synthesis

We report multi-armed/dendritic molecules having unsaturated side chains for generating scratch-free, self-standing cross-linked transparent films with embedded metal nanoparticles via autoxidation induced in situ synthesis.

Anions of dithiouracil and trithiocyanuric acid as bridges in polynuclear titanium(III) metallocenes: the X-ray crystal structure of pyrimidine-2,4-dithiolatobis[bis(η5-methylcyclopentadienyl)titanium(III)]

The preparation and magnetic properties are reported for five compounds which incorporate the anions of 2,4-dithiouracil, 2-thiouracil, 4,6-dithiopyrimidine, 4,6-dihydroxypyrimidine, or trithiocyanuric acid as chelating bridges between bis(methylcyclopentadienyl)-titanium(III) units; the single crystal structure of pyrimidine-2,4-dithiolatobis[bis(η5-methylcyclopentadienyl)-titanium(III)] is reported.

Coordination and valence of europium in [Eu(α-2-As2W17O61)2]17− and [Eu(W5O18)2]9−

Abstract Europium L3 edge X-ray absorption fine structure (XAFS) spectroelectrochemistry was used to determine the valence of europium in [Eu(α-2-As2W17O61)2]17− and [Eu(W5O18)2]9−. Dilute solutions of these anions in aqueous supporting electrolytes were examined at ambient temperature and at extreme potentials. In situ XANES (X-ray absorption near edge structure) data revealed that Eu is trivalent in both [Eu(α-2-As2W17O61)2]17− and [Eu(W5O18)2]9− at rest potential. Furthermore, it was not reduced to Eu2+ by constant-potential bulk electrolysis at significantly reducing potentials under the electrochemical conditions used herein. These results stand in obvious contrast to the redox behavior of [EuP5W30O110]12−, in which Eu3+ is reduced to Eu2+ under similar electrochemical conditions.

Synthesis, characterization and solid state structure of a neutral gallium(III) amino thiolate complex: a potential radiopharmaceutical for PET imaging

The neutral gallium complex of a bisaminoethanethiol ligand has a square pyramidal coordination geometry with Ga–N and Ga–S bonds.

Lanthanide complexes of polyoxometalates: characterization bytungsten-183 and phosphorus-31 nuclear magnetic resonancespectroscopy

Lanthanide complexes of three classes of polyoxoanions have been characterized by multinuclear ( 183 W and 31 P) NMR spectroscopy among other techniques. The tetrabutylammonium salt of the lacunary [α-2-P 2 W 17 O 61 ] 10- , prepared by metathesis of the potassium salt, was isomerically pure according to 183 W and 31 P NMR spectroscopy. The K 13 [Ln(SiW 11 O 39 ) 2 ] family of complexes show a six-line pattern in the 183 W NMR spectrum at 40 °C for the lanthanum derivative, consistent with a symmetrical structure (C 2h or C 2v symmetry), and eleven-line patterns for the ytterbium and lutetium analogues at 23 °C, suggesting a lower symmetry (C 2 ) for complexes of the heavier lanthanide ions. The same phenomenon was observed for the [α-2-Ln(P 2 W 17 O 61 ) 2 ] 17- family of compounds. High-temperature 183 W NMR experiments on the [Lu(SiW 11 O 39 ) 2 ] 13- and the [α-2-Lu(P 2 W 17 O 61 ) 2 ] 17- compounds showed a reversible broadening and coalescence of the resonances, due to a dynamic effect, possibly rotation of the oxoanion ligands.