Development of theranostic somatostatin analogues for the treatment of neuroendocrine tumors

Over the past decades somatostatin-based radiopharmaceuticals (e.g. [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE) have been used to diagnose and treat neuroendocrine tumor (NET) patients with great success [5,8]. [18F]AlF-NOTA-octreotide, a promising 18F-labeled somatostatin analogue and potential alternative for 68Ga-DOTA-peptides, has recently been shown to be a viable clinical alternative [11,213]. Ideally, the same precursor (combination of chelator-linker-vector) should be used for production of both diagnostic and therapeutic radioprobes with very similar (e.g. Al18F/213Bi/177Lu) or identical (e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing accurate, personalised dosimetry estimation and radionuclide therapy of NET patients [10,20]. In this study we evaluated the versatile and highly effective chelators 3p-C-NETA and 3p-C-DEPA [80] as potential theranostic agents capable of complexing both diagnostic and therapeutic radionuclides, including β- and α-emitters. As a proof-of-principle, 3p-C-NETA-TATE was investigated as a theranostic agent for NETs and finally, a SSTR agonist and antagonist were evaluated to identify the optimal vector molecule for efficient in vivo targeting of NETs. In chapter II we demonstrated the versatility of 3p-C-NETA as excellent chelator for diagnostic applications employing the well-established Al18F-method and therapeutic applications using 177Lu, 213Bi and 161Tb. As a proof-of-principle, [18F]AlF-3p-C-NETA-TATE was synthesized in good radiochemical yield with excellent radiochemical purity. The compound showed promising in vivo biodistribution properties in rats using μPET/MR. In chapter III we showed the superior in vitro SSTR2 cell binding properties of the SSTR antagonist [18F]AlF-NOTA-JR11 compared to the agonist [18F]AlF-NOTA-octreotide. In vivo tumor uptake of the two radiotracers was however comparable. In chapter IV we successfully demonstrated the diagnostic ([18F]AlF) and therapeutic (177Lu and 213Bi) potential of our precursor 3p-C-NETA-TATE. 3p-C-NETA-TATE has demonstrated to be a promising chelator/vector molecule combination for theranostic applications for NETs. However, further preclinical evaluation of the therapeutic counterparts, including therapeutic efficacy studies, are needed to proceed with clinical translation. 3p-C-NETA has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine. Finally, in chapter V we demonstrated the excellent radiolabeling properties of 3p-C-DEPA with 225Ac using mild conditions, making it an interesting agent to be considered for 225Ac-labeling of heat-sensitive molecules. However, additional studies are warranted to evaluate the stability of the 225Ac-labeled vector molecule.