Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

Abstract

(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA5m.SA.KuE and AAZTA5.SA.KuE were synthesized. DATA5m.SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA5m.SA.KuE was synthesized successfully. AAZTA5.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA5m.SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [68Ga]Ga-DATA5m.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA5.SA.KuE and DATA5m.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [177Lu]Lu-AAZTA5.SA.KuE, [44Sc]Sc-AAZTA5.SA.KuE and [68Ga]Ga-DATA5m.SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use.

Cold Kit Labeling: The Future of 68Ga Radiopharmaceuticals?

“…PSMA binding motif lysine-urea-glutamate (KuE) has been attached to a THP chelator in yet another investigational kit, which was recently the object of a phase 2 trial ( 120 ). The same motif was also successfully grafted on DATA 5M and AAZTA 5 chelators, but no kit formulation has been reported to date, although it is amenable to do ( 121 ).…”

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications

“…This work highlighted the highly versatile labeling properties of AAZTA 5 -SA-PSMA for several radiometals, suggesting the significant value of the AAZTA-SA building block in the design of new radiopharmaceuticals candidates. A DATA 5m analogue of this latter molecule, named DATA 5m -SA-KuE, was also synthesized and radiolabeled with 68 Ga [76]. Interestingly, reaction heating was necessary to reach high RCYs, especially when small amounts of vector were used.…”

AAZTA‐Like Ligands Bearing Phenolate Arms as Efficient Chelators for 68Ga Labelling in vitro and in vivo

“…[21,[23][24][25][26] Modifications of the AAZTA structure were designed to obtain more rigid backbones such as in CyAAZTA [27,28] and PIDAZTA [29] (Figure 1), and thus more inert Ga(III) complexes, or to lower the denticity obtaining the hexadentate DATA ligands (Figure 1) to allow a better match with the hexacoordinate Ga(III) ion. [20] DATA m bifunctional derivatives were also conjugated to targeting vectors such as PSMA [30] or fibroblast activation protein inhibitor (FAP) [31] for tumour imaging. However, the success of AAZTA and derivatives is weakened by the formation of a hydroxo-species at physiological pH that sometimes accelerates the metal dissociation rate as well as worsening radiolabelling performance.…”