Synthesis and Validation of Novel Chelates for Gallium-68 PET Imaging

Price, Thomas

Abstract

Background:
The use of gallium-68 (68Ga) in positron emission tomography (PET) imaging is currently of great interest. This radionuclide can be produced from a small generator allowing easy access to this imaging tool. Recently, [68Ga][Ga(DOTATATE)] has been approved for clinical application for the diagnosis of neuroendocrine tumours (NETs) highlighting the value of 68Ga PET imaging.
The standard macrocyclic chelators that are radiolabelled with 68Ga require acidic conditions, and often also require heating to high temperatures, to achieve high radiochemical yields (RCYs) in short times. Recent developments in 68Ga radiolabelling have sought to achieve high RCYs without the need for heating and at neutral pH. To this end, recent chelator designs have been open chain ligands rather than the more traditional macrocyclic designs.
Aims:
The aims of this thesis are to develop new acyclic chelators for Ga(III); to synthesise their Ga(III) complexes, to radiolabel these chelators with 68Ga, and to assess the stability of these complexes.
Results:
Six novel chelators, and nine novel Ga(III) systems, were prepared and investigated.
The hexadentate ligand, H3Dpaa, along with 3 bifunctional derivatives, was shown to form a complex with Ga(III) in which only 5 of the coordinating sites are occupied by the ligand. The remaining site is occupied by water. These chelators could be radiolabelled efficiently with 68Ga, achieving RCYs of 85-95% at pH 7.4. The resulting complexes were assessed for their thermodynamic stabilities with logKGa-L of 16.13-18.53. Decomplexation was complete within 30 minutes incubation with foetal bovine serum (FBS).
Complexation of Ga(III) by the heptadentate chelator H3Tpaa saturated the coordination sphere of Ga(III). This chelator was radiolabelled with an RCY >95% at pH 7.4. When assessed for stability to FBS, 32% of this system remained intact after 30 minutes. However, decomplexation was complete within 2 hours. Further derivatives were prepared; while they could be radiolabelled, the complexes formed were not stable to FBS.
The novel chelator, H3Bn2DT3A, complexes Ga(III) in a hexadentate manner, forming a mer complex with logKGa-L = 18.25. H3Bn2DT3A was radiolabelled with RCYs >80% across a wide pH range. This system showed a pH dependent speciation. No decomplexation of the species formed above pH 5.5 was seen over 2 hours when incubated with FBS. Formation of this species was promoted at pH 6-8, by high temperature, high ligand concentration, and with a long reaction time. A bifunctional analogue was prepared but the resulting 68Ga complex formed was not stable to FBS.
Conclusions:
While capable of being radiolabelled efficiently across a wide pH range, tripodal picolinate Ga(IIII) complexes have poor FBS stability making them unsuitable for application in vivo. This is likely due to the rigid nature of the picolinate arms preventing the optimal coordination geometry being achieved; this is highlighted in the case of the H3Dpaa family due to the unsaturated coordination sphere and bound water molecule.
The use of a more flexible chelator, H3Bn2DT3A, allowed for the formation of a serum stable 68Ga complex, although the flexibility also resulted in multiple species being formed. This system has a number of sites that can be varied in the future for further optimisation of the radiolabelling conditions and for development of bifunctional derivatives. The site tested here for conjugation; the central acetate arm, resulted in a less kinetically stable system and future work should investigate alternate sites of conjugation.

Citation

Price, T. Synthesis and Validation of Novel Chelates for Gallium-68 PET Imaging. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4743579

• Thesis Type: Thesis
• Deposit Date: Jul 25, 2024
• Publicly Available Date: Jul 31, 2024
• Public URL: https://hull-repository.worktribe.com/output/4743579
• Additional Information: Biomedical Sciences; University of Hull
• Award Date: Jul 1, 2019