Synthesis and evaluation of 18F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography

Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging

Novel radiolabeled peptides to improve breast and prostate cancer diagnosis by PET

In the past years, peptide based radiopharmaceuticals have turned into favorable molecular imaging agents for specific targeting of cancer. This is mainly because many tumors happen to overexpress certain regulatory peptide receptors. For instance, the gastrin releasing peptide (GRP) receptors are overexpressed in prostate cancer–the most common malignancy among men–and somatostatin 2a (SST2a), and neuropeptide Y1 (NPY1) receptors are overexpressed in breast cancer–the most common cancer among women. There are disadvantages to most existing imaging techniques used for early detection of prostate and breast cancer. Thus, the objective of the work presented in this thesis was to develop a novel and specific diagnostic approach using radiolabeled peptides for PET imaging to localize lesions of breast and prostate cancers. Towards this end, different derivatives of GRP, SST2a, and NPY1 peptides were synthesized and their binding affinity was confirmed in vitro. The promising candidates were radiolabeled with ¹⁸F or ⁶⁸Ga–the ideal radioisotopes in PET applications. Two different ¹⁸F labeling methods (click chemistry and trifluoroborate exchange reaction) were conducted. Finally, the biological evaluation of radiopharmaceuticals was performed in vivo by using animal models of prostate and breast cancer. In the click chemistry approach, introducing PEG spacers to GRP derivatives improved the in vitro properties and the pharmacokinetics in the prostate tumor model, leading to better tumor visualization by PET imaging. The trifluoroborate exchange reaction proved to be a superior technique–by both radiochemistry and biological criteria–in GRP labeling, resulting in an excellent tumor uptake with ¹⁸F-AmBF3-MJ9. The same approach was also successful for targeting SST2a receptors in mice bearing rat pancreatic tumor cells. The data achieved with this labeling method suggest the potential application of these radiopharmaceuticals for diagnosis in cancer patients. A high tumor to background ratio was achieved in the Zr-75-1 tumor model with ⁶⁸Ga-DOTA-TATE and ⁶⁸Ga-NODAGA-LM3. Hence, this cell line is a promising breast cancer model for SST2a imaging. The NPY1R compound ¹⁸F-ALK-BVD15 was not metabolically stable and showed low receptor-mediated tumor uptake in NPY1R-positive tumors. Different strategies will need to be explored in order to modify and improve the stability of the peptide.Medicine, Faculty ofGraduat

Synthesis and evaluation of 18

Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging