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 NETs patients with great success. Al18F-NOTA-octreotide, a promising 18F-labeled somatostatin analogue and potential alternative for 68Ga-DOTA-peptides, is under clinical evaluation. Ideally, the same precursor (combination of chelator-linker-vector) can 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.
In this study we evaluated the versatile and highly effective chelators 3p-C-NETA and 3p-C-DEPA 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, 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 providing excellent radiochemical purity and promising in vivo biodistribution properties 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. However, in vivo tumor uptake of the two radiotracers was comparable and limited bone uptake was observed, indicating excellent in vivo stability.
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 vector molecule for theranostic applications for neuroendocrine tumors. 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 IV 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.
Frederik Cleeren (KULEUVEN)
- Christophe Deroose (KULEUVEN)
- Thomas Cardinaels (KULEUVEN)
SCK CEN mentors:
Maarten Ooms (SCK CEN)
Click here for a list of obtained PhD degrees.