Malik Noeen, Baur Benjamin, Winter Gordon, Reske Sven N, Beer Ambros J, Solbach Christoph
Clinic for Nuclear Medicine, University Hospital Ulm, Ulm, Germany.
Mol Imaging Biol. 2015 Dec;17(6):777-85. doi: 10.1007/s11307-015-0844-6.
Ga-68-labeled prostate-specific membrane antigen (PSMA) ligands have been used clinically for positron emission tomography (PET) imaging of prostate cancer. However, F-18-labeled compounds offer several advantages, including the potential for delayed imaging, high starting activities enabling multidose preparation, and improved spatial resolution in PET. For F-18 labeling of peptides conjugated with a suitable chelator, a fast and feasible method is the use of Al(18)F. In the present study, the radiofluorinations of a well-known PSMA ligand Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (PSMA-HBED) via Al(18)F were performed with respect to various reaction parameters, along with the biological evaluations in a cell experiment.
[Al(18)F]PSMA-HBED was prepared by adding Na[(18)F]F into a vial containing 0.026 μmol peptide (in 0.05 M NaOAc buffer) and 0.03 μmol AlCl3⋅6H2O (in 0.05 M NaOAc buffer). Then, it was stirred at different temperatures from 1 to 30 min. Afterwards, purification was carried out by solid phase extraction. Biological evaluations were performed in PSMA-positive cell lines LNCaP C4-2, along with a negative control using PC-3 cell lines.
The best labeling results (81 ± 0.5 %, n = 4) were observed with 0.026 μmol peptide (30 °C, 5 min). For preclinical experiments, the production of [Al(18)F]PSMA-HBED at 35 °C including purification by solid phase extraction (SPE) succeeded within 45 min, resulting in a radiochemical yield of 49 ± 1.2 % (decay-corrected, n = 6, radiochemical purity ≥98 %) at EOS. The labeled peptide revealed serum stability for 4 h as well as a promising binding coefficient (K D) value of 10.3 ± 2.2 nM in cell experiments with PSMA-positive LNCaP C4-2 cells.
An efficient and one-pot method for the radiosynthesis of [Al(18)F]PSMA-HBED was developed (0.26 μmol of precursor at 35 °C). In cell culture studies, the K D suggests [Al(18)F]PSMA-HBED as a potential PSMA ligand for future investigations in vivo and clinical applications afterwards.
镓 - 68 标记的前列腺特异性膜抗原（PSMA）配体已在临床上用于前列腺癌的正电子发射断层扫描（PET）成像。然而，氟 - 18 标记的化合物具有多种优势，包括延迟成像的潜力、可实现多剂量制备的高起始活度以及 PET 中更好的空间分辨率。对于与合适螯合剂共轭的肽进行氟 - 18 标记，一种快速可行的方法是使用Al(18)F。在本研究中，针对各种反应参数，通过Al(18)F对一种知名的 PSMA 配体谷氨酸 - 氨基 - 羰基 - 氨基 - 赖氨酸（Ahx） - HBED - CC（PSMA - HBED）进行了放射性氟化，并在细胞实验中进行了生物学评估。
通过将 Na[(18)F]F 添加到含有 0.026 μmol 肽（在 0.05 M 醋酸钠缓冲液中）和 0.03 μmol 六水合氯化铝（在 0.05 M 醋酸钠缓冲液中）的小瓶中来制备[Al(18)F]PSMA - HBED。然后，在 1 至 30 分钟的不同温度下搅拌。之后，通过固相萃取进行纯化。在 PSMA 阳性细胞系 LNCaP C4 - 2 中进行生物学评估，并使用 PC - 3 细胞系作为阴性对照。
在 0.026 μmol 肽（30°C，5 分钟）的条件下观察到最佳标记结果（81±0.5%，n = 4）。对于临床前实验，在 35°C 下制备[Al(18)F]PSMA - HBED 并通过固相萃取（SPE）纯化在 45 分钟内成功完成，在实验结束时放射性化学产率为 49±1.2%（衰变校正，n = 6，放射性化学纯度≥98%）。在与 PSMA 阳性的 LNCaP C4 - 2 细胞的细胞实验中，标记的肽显示出 4 小时的血清稳定性以及有前景的结合系数（KD）值 10.3±2.2 nM。
开发了一种高效的一锅法用于[Al(18)F]PSMA - HBED 的放射性合成（35°C 下 0.26 μmol 前体）。在细胞培养研究中，KD 表明[Al(18)F]PSMA - HBED 作为一种潜在的 PSMA 配体，可用于未来的体内研究及后续临床应用。
