HTA Co., Ltd., CAEA Center of Excellence on Nuclear Technology Applications for Engineering and Industrialization of Radiopharmaceuticals, CNNC Engineering Research Center of Radiopharmaceuticals, Beijing, China.
HTA Co., Ltd., CAEA Center of Excellence on Nuclear Technology Applications for Engineering and Industrialization of Radiopharmaceuticals, CNNC Engineering Research Center of Radiopharmaceuticals, Beijing, China; Biomedical Engineering Department, Huazhong University of Science and Technology, Wuhan, China.
Eur J Pharm Sci. 2024 Feb 1;193:106671. doi: 10.1016/j.ejps.2023.106671. Epub 2023 Dec 16.
A novel F-radiolabeled somatostatin analogue, [AlF]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [AlF]NODA-MPAA-HTA was designed and synthesized by conjugating F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors.
The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [AlF]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for AlF labeling of chelating agent-biomolecule conjugates was used to synthesize [AlF]NODA-MPAA-HTA. In vitro stabilities of [AlF]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2 h. Ex vivo biodistribution and in vivo imaging of [AlF]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging.
[AlF]NODA-MPAA-HTA was synthesized using a one-step F-AlF labeling procedure resulting in moderate radiochemical yield (60-80 %, non-decay corrected) and high radiochemical purity (>95 %). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/μmol. At 30 min and 60 min, the uptake of [AlF] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47 ± 0.97 %/105 cells and 12.11 ± 0.32 %/105 cells, respectively. The affinity of [AlF]NODA-MPAA-HTA for SSTR2 was determined to be 8.77 ± 1.14 nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [AlF]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [AlF]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of AlF-labeled somatostatin analogues as tumor probes for PET imaging of NETs.
Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8 min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [AlF]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel F-labeled somatostatin analogue, [AlF]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.
合成了一种新型 F 放射性标记的生长抑素类似物 [AlF]NODA-MPAA-HTA，用于神经内分泌肿瘤（NETs）的正电子发射断层扫描（PET）成像。[AlF]NODA-MPAA-HTA 通过将 F 核与经过修饰的 KE108 肽（一种对所有五种生长抑素受体（SSTR1-5）具有高亲和力的生长抑素类似物）偶联，设计并合成了 [AlF]NODA-MPAA-HTA，其中通过连接双功能螯合剂（NODA）来靶向生长抑素受体（SSTR）阳性肿瘤。
KE108 肽的氨基与 NODA 的羧基通过缩合反应偶联，得到[AlF]NODA-MPAA-HTA 的标记前体，其前体通过 Fmoc 固相方法获得。使用一种新的用于螯合剂-生物分子缀合物的 AlF 标记方法来合成 [AlF]NODA-MPAA-HTA。通过在生理盐水或牛血清中孵育 2 小时，评估[AlF]NODA-MPAA-HTA 的体外稳定性。进一步研究[AlF]NODA-MPAA-HTA 的体外生物分布和体内成像，以评估其 SSTR 靶向能力和使用 PET 成像诊断 NETs 的可行性。
使用一步 F-AlF 标记程序合成了 [AlF]NODA-MPAA-HTA，得到了中等的放射化学产率（60-80%，未衰变校正）和高的放射化学纯度（>95%）。它表现出良好的亲水性和优异的体外稳定性，摩尔活性为 122GBq/μmol。在 30 分钟和 60 分钟时，[AlF]NODA-MPAA-HTA 在 HEK293-SSTR2 细胞中的摄取率分别为 5.47±0.97%/105 个细胞和 12.11±0.32%/105 个细胞。[AlF]NODA-MPAA-HTA 对 SSTR2 的亲和力确定为 8.77±1.14nM。在 HEK293-SSTR2 肿瘤荷瘤小鼠的微 PET 成像中，[AlF]NODA-MPAA-HTA 显示出高肿瘤放射性摄取和高肿瘤与肌肉的比值。生物分布结果证实，肿瘤的放射性摄取明显高于肌肉，超过五倍（P<0.001）。此外，[AlF]NODA-MPAA-HTA 相对较低的骨摄取表明在体内没有发生脱氟反应。这些初步结果为进一步研究 AlF 标记的生长抑素类似物作为 NETs 的 PET 成像肿瘤探针提供了实验证据。
氟-18 广泛用作正电子发射断层扫描（PET）生产放射性药物的放射性核素。由于其半衰期短（T1/2，109.8min），易于生产，将有助于这种放射性药物的广泛传播。我们合成了一种高质量的[AlF]NODA-MPAA-HTA，产率令人满意。这种放射性药物显示出更高的肿瘤摄取和更好的肿瘤与肌肉对比度，从而获得了出色的图像质量。这些发现表明，新型 F 标记的生长抑素类似物[AlF]NODA-MPAA-HTA 是 NETs 的 PET 成像的有前途的工具。
