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.
Highlights
Prostate-specific membrane antigen (PSMA) has become a very popular target in the diagnosis and treatment of prostate cancer in the last decade
In the central nervous system, PSMA acts as NAALADase, which cleaves the glutamate moiety from the neurotransmitter N-acetyl aspartyl glutamate
The PSMA binding affinity of DATA5m.SA.KuE and AAZTA5.SA.KuE, as well as PSMA-11, was determined in a competitive radioligand assay using PSMA-positive LNCaP cells that were incubated with 0.75 nM [68Ga]Ga-PSMA-10 in the presence of 12 increasing concentrations of the non-labeled SA-conjugated compounds
Summary
Prostate-specific membrane antigen (PSMA) has become a very popular target in the diagnosis and treatment of prostate cancer in the last decade. In the proximal small intestine, this enzyme, called folate hydrolase FOLH1, releases glutamate residues from poly-glutamated folate [1,2] Besides these physiological functions, PSMA seems to play an important role in prostate carcinogenesis since it is highly expressed in prostate tumor cells. The isocyanate was reacted with tert-butyl protected glutamate and the protected PSMA inhibitor lysine-urea-gluta5mofa1t8e 10 was obtained and followed by reductive deportation of the lysine side chain, yielding 11. The isocyanate was reacted with tert-butyl protected glutamate and the protected PSMA inhibitor lysine-urea-gluta5mofa1t8e was obtained and followed by reductive deportation of the lysine side chain, yielding This compound was coupled to SADE in phosphate buffer at pH 7.
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