Abstract
BackgroundDue to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for 18F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-18F-FBOA (1) and EuE-k-β-a-18F-FPyl (2), both with optimized linker structure and different 18F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with 18F-DCFPyl and 18F-PSMA-1007.ResultsRadiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67 ± 7 and 53 ± 7%, d.c.) and purity (> 98%). When compared with 18F-DCFPyl (IC50 = 12.3 ± 1.2 nM) and 18F-PSMA-1007 (IC50 = 4.2 ± 0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC50 = 4.2 ± 0.4 nM (1), IC50 = 1.1 ± 0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7 ± 2.0% IA/g, (2) 13.0° ± 1.0% IA/g vs. 7.3 ± 1.0% IA/g (18F-DCFPyl), 7.1 ± 1.5% IA/g (18F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP = − 1.6) and high plasma protein binding (98%), 18F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, 18F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2).ConclusionBoth 18F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced 18F-PSMA-1007 and 18F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable 18F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.
Highlights
Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands
The respective labeling precursors were cleaved from the resin using trifluoroacetic acid (TFA), with concomitant removal of acid labile protecting groups (54–63% yield after reversed phase high-performance liquid chromatography (RP-HPLC) purification)
The corresponding cold reference ligands EuE-k-β-a-FPyl, FDCFPyl, and F-PSMA-1007 were subsequently prepared by direct conjugation of the respective precursors with 2,3,5,6-tetrafluorophenyl 6-fluoronicotinate under basic conditions and were obtained in 82, 75, and 87% yield after RP-HPLC purification, respectively
Summary
Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. During the last several years, the prostate-specific membrane antigen (PSMA) and corresponding radiolabeled inhibitors have become one of the most extensively investigated target/tracer pair for molecular imaging and radioligand therapy of prostate cancer (PCa). Due to readily availability of 68Ge/68Ga-generators, strong emphasis has been placed on the development and optimization of 68Ga-labeled PET probes for clinical imaging of PCa. the use of 68Ga for labeling of PSMA inhibitors has severe limitations. Due to the unique radionuclide characteristics of 18F (t1/2 = 109.7 min, Eß+ = 0.63 MeV) and its corresponding advantages for clinical PET imaging combined with largescale production by means of even small cyclotrons, several groups have focused on the development of 18F-labeled PSMA inhibitors for PCa imaging [1,2,3,4,5,6].
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