Production and utilization of unconventional radiometals for advanced diagnostics and therapy

Abstract

The continued development in biochemistry delivers vectors capable of specifically identifying foreign entities like malignancies and infections. Many of these vectors have long circulation time in vivo, resulting in optimal biodistribution for imaging several days post injection. The diagnostic potential of these can only be fully utilized if non-standard radionuclides with half-lives extending beyond those of the standard catalogue (11C, 18F, and 64Cu) are available. As for therapy, the increased specificity of new vectors strengthens the argument for using targeted radionuclide therapy, as they allow delivery of therapeutic doses to target tissues with minimal unspecific uptake and dose in healthy non-target tissues. This allows for the use of a wider range of radionuclides, like α-emitters, for which high specificity is needed due to their high toxicity. The development of highly specific, internalizing vectors opens for use of Auger emitters. The therapeutic effect of these radionuclides most likely relies on internalization and translocation to the cell nucleus, because of their extremely localized, short-range dose deposition. Although the selection such vectors is still limited, the development of robust production methods for Auger emitters is crucial for investigating the basic principles of Auger therapy. The focus of this thesis has been expanding the number of isotopes and techniques available in the nuclear medicine toolbox. The work performed using diagnostic isotopes includes: 52Mn: A production and separation method for high specific activity 52Mn was developed. Labeling conditions and serum stability for 52Mn-DOTA were investigated, and 52Mn was labeled to intact antibodies showing in vivo stability in mice. 89Zr: Very high specific activity 89Zr was produced. A labeling method for sensitive metalloproteins was developed. Further, the potential pitfalls in quality control of 89Zr labeled proteins were documented. 45Ti: A production and separation method for 45Ti was developed and optimized. This work includes one of the first ever in vivo studies of a 45Ti-compound. The work performed using therapeutic isotopes includes: 177Lu: The sensitive metalloprotein FVIIai was conjugated with the chelator cDTPA and labeled with 177Lu for a therapeutic study. This included optimization of labeling conditions and development of quality control. 135La: Pressed Ba-targets were produced and production and separation methods for high specific activity 135La were developed. Labeling conditions were tested and cellular and human dosimetry of 135La was calculated. 165Er: A production method for 165Er was developed, based on electron-capture-mediated release of 165Er from DOTA. Finally, a method was developed using 140Nd for assaying cellular internalization of a compound in vivo. General dosimetry calculations and considerations are further presented to aid selection of the radionuclide when designing a radiopharmaceutical. The combined work serves to aid further development in both pharmaceutical research, and diagnostic as well as therapeutic applications of radionuclides.