Five Eleven Pharma Inc., Philadelphia, Pennsylvania 19104, United States.
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Bioconjug Chem. 2021 May 19;32(5):1017-1026. doi: 10.1021/acs.bioconjchem.1c00177. Epub 2021 Apr 19.
Prostate-specific membrane antigen (PSMA)-targeted radioligands have played an increasing role in the diagnosis of prostate cancer. [Ga]Ga-P16-093 is a PSMA-targeting agent for positron emission tomography imaging, currently under a Phase 2 clinical trial. In the present study, P16-093 was labeled with F via [F]AlF complex formation, and the biological properties of [F]AlF-P16-093 were evaluated. Optimization of radiolabeling efficiency was performed by testing a series of parameters, including the amount of free ligand; the amount of Al; and the influence of solvent, pH, temperature, reaction time, and reaction volume. Optimal labeling results were achieved at pH 5 by reacting at 60 °C for 15 min in a vial containing 74-370 MBq of [F]fluoride, 46 nmol of P16-093, 40 nmol of AlCl·6 HO, and 50% EtOH. [F]AlF-P16-093 was prepared with a non-decay-corrected radiochemical yield of 54.4 ± 4.4% ( = 9) within 30 min (final radiochemical purity ≥95%). In vitro, [F]AlF-P16-093 showed PSMA-specific high uptakes in PIP-PC3 cells. The binding affinity of [F]AlF-P16-093 to PSMA was determined as of 12.4 ± 2.0 nM. The tumor uptake in mice with a xenografted PSMA-expressing PIP-PC3 tumor was high (18.8 ± 5.14% ID/g at 1 h postinjection) and retained without washout for 2 h. In addition, tumor uptake was almost completely blocked by coinjecting a PSMA inhibitor, 2-PMPA. The bone activity at 1 h post injection was higher with [F]AlF-P16-093 (2.83 ± 0.49% ID/g) in comparison to that of [Ga]Ga-P16-093 (0.26 ± 0.07% ID/g). In summary, an efficient and simple radiosynthesis of [F]AlF-P16-093 was achieved. [F]AlF-P16-093 showed desirable in vivo pharmacokinetics and excellent PSMA-targeting properties for imaging PSMA expression in prostate cancer.
前列腺特异性膜抗原（PSMA）靶向放射性配体在前列腺癌的诊断中发挥了越来越重要的作用。[Ga]Ga-P16-093 是一种用于正电子发射断层扫描成像的 PSMA 靶向剂，目前正在进行 2 期临床试验。在本研究中，通过[F]AlF 络合物的形成将 F 标记到 P16-093 上，并评估了[F]AlF-P16-093 的生物学特性。通过测试一系列参数，包括游离配体的量；Al 的量；以及溶剂、pH 值、温度、反应时间和反应体积的影响，优化了放射性标记效率。在 pH 5 下，在含有 74-370 MBq [F]氟化物、46 nmol P16-093、40 nmol AlCl·6 HO 和 50% EtOH 的小瓶中，于 60°C 反应 15 min，可获得最佳标记结果。[F]AlF-P16-093 的非衰变校正放射性化学产率为 54.4±4.4%（n=9），在 30 min 内（最终放射性化学纯度≥95%）。体外，[F]AlF-P16-093 在表达 PSMA 的 PIP-PC3 细胞中表现出 PSMA 特异性高摄取。[F]AlF-P16-093 与 PSMA 的结合亲和力为 12.4±2.0 nM。在具有过表达 PSMA 的 PIP-PC3 肿瘤的异种移植小鼠中，肿瘤摄取率较高（注射后 1 小时为 18.8±5.14% ID/g），2 小时内无洗脱。此外，用 PSMA 抑制剂 2-PMPA 注射几乎完全阻断了肿瘤摄取。与[Ga]Ga-P16-093（0.26±0.07% ID/g）相比，[F]AlF-P16-093 在注射后 1 小时的骨活性更高（2.83±0.49% ID/g）。总之，实现了[F]AlF-P16-093 的高效简便放射性合成。[F]AlF-P16-093 表现出理想的体内药代动力学特性和优异的 PSMA 靶向特性，可用于成像前列腺癌中的 PSMA 表达。
