Synthesis and Development of Diagnostic Tools for Medical Imaging

The need for novel diagnostic tools in medical imaging is increasing since they can improve the positive therapeutic outcome as well as patient compliance. In this thesis different diagnostic tools were developed within an interdisciplinary project, whereas the main work reported in this thesis was the synthesis of different materials. The first project introduces the development of injectable fiducial markers within the field of image-guided radiotherapy. Fiducial markers for computed tomography (CT)-imaging are today needed in order to correlate the positioning of the tumor to provide a more precise and improved radiation, as tumors rarely display a fixed position during radiotherapy. A fiducial marker based on encapsulated gold nanoparticles within the gelation matrix of sucrose acetate isobutyrate (SAIB) was developed and tested in vivo. The scientific objective was to provide sufficient surface engineering of the gold nanoparticles that will allow full dispersion of AuNPs within the hydrophobic environment of the SAIB matrix. As stabilizing coating-materials PEG, PNIPAM polymers and a dithiolane SAIB derivative were tested. The unique gelation properties of the SAIB matrix led to the second project of injectable fiducial tissue markers for surgical guidance of non-palpable tumors and brachytherapy. As radioactive tracer, radioiodinated SAIB-derivatives were developed based on the regioselective ipso-iodination of aryl-TMS moieties. Radioiodination was conducted under carrier free conditions in high radiochemical yields by Tl(OOCCF₃)₃ and [¹²⁵]NaI. The application of the radiolabeled 125I-SAIB derivative was tested in vivo as a tissue marker for surgical guidance and evaluated in terms of dosimetry. The third project involved the synthesis of iodide-based contrast agents designed for remote loading of liposomes. Long circulating contrast agents for blood pool imaging by CT-imaging are of interest due to the current limitations of short retention times and the considerable amounts needed to achieve a proper contrast. A small library of contrast agents designed for remote loading of liposomes was synthesized. Remote loading of one candidate was successful; however, the proper contrast level was not sufficient to be visible by CT-imaging. Another diagnostic tool for blood pool imaging is DOTA-modified pluronic/cyclodextrin (CD)-based polyrotaxanes (PRs). With the previously reported chelation of Gd and the prolonged retention time of Gd-chelated Pluronic/CD PRs, the aim was to extend the use of DOTA-modified Pluronic/CD-based PRs as positron emitting agents by chelation of ⁶⁴Cu. Pluronic/CD-based PRs grafted with DOTA was synthesized in the fourth project. The last project deals with the site-specific radioiodination of peptides and proteins.To achieve a conclusive outcome in radioimmunoassays as well as retaining a high binding affinity of receptor binging peptides, the regioselective radioiodination is crucial. Therefore, a TMS-substituted tyrosine was synthesized via the Negishi coupling to test if regioselective iodination could be obtained. The tyrosine derivative was used in the synthesis of dipeptides of phenylalanine, tyrosine and tryptophan respectively in order to evaluate the selectivity towards the ipso-substitution of the TMS in the iodination reaction. First proof-of-concept experiments using aryl-TMS as placeholder in the site-specific iodination of peptides and proteins have been demonstrated.