Purpose: A novel F-18-radiolabeled somatostatin analogue, [(AlF)-F-18]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [(AlF)-F-18]NODA-MPAA-HTA was designed and synthesized by conjugating F-18 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.Methods: 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)-F-18]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for (AlF)-F-18 labeling of chelating agent-biomolecule conjugates was used to synthesize [(AlF)-F-18]NODA-MPAA-HTA. In vitro stabilities of [(AlF)-F-18]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)-F-18]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging.Results: [(AlF)-F-18]NODA-MPAA-HTA was synthesized using a one-step F-18-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/mu mol. At 30 min and 60 min, the uptake of [(AlF)-F-18] 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)-F-18]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)-F-18]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)-F-18]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of (AlF)-F-18-labeled somatostatin analogues as tumor probes for PET imaging of NETs.Conclusion: 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)-F-18]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-18-labeled somatostatin analogue, [(AlF)-F-18]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.

Gallium ［68Ga］ is an important positron-emitting radionuclide in PET imaging radiopharmaceuticals. In order to ensure that the quality of gallium ［68Ga］ solution, a key raw material of gallium ［68Ga］ radiopharmaceuticals, meets the requirements of high labeling efficiency and safety, a detailed study on impurities in gallium ［68Ga］ solution from the generator was carried out, analytical method for impurity detection was developed and the validation of the methodology was completed. To control radiochemical impurities, radioactive thin-layer chromatography (Radio-TLC) method was used. The effects of key variables such as mobile phase, pH of the mobile phase, and system suitability solution on the test results were studied. After method optimization, iTLC-SG was determined to be the stationary phase, methanol-1 mol/L ammonium acetate (1∶1, V/V, ammonium acetate pH=2.8±0.2) as the mobile phase. In order to control elemental impurities, twelve elements including Fe, Ni, Zn, Sb, Pb, Li, V, Co, Cu, As, Cd, and Hg were determined by inductively coupled plasma mass spectrometry (ICP-MS) method. The radionuclide purity was determined by high-purity germanium (HPGe) γ spectroscopy, and the γ nuclide impurities such as 68Ge were controlled. Combined with the properties of the samples and the characteristics of each analytical method, the established analytical methods were validated. The validation included system suitability and resolution, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision, durability, etc. These validated methods were used to determine impurities in gallium-［68Ga］ chloride solutions. The impurity test results of gallium-［68Ga］ chloride solution show that the Rf of 68Ga3+ is ≤0.2, and its radiochemical purity is 99.04%±0.35% (n=3). Its iron content is ≤0.5 μg/GBq, zinc content is ≤0.1 μg/GBq, and other elements do not exceed 30% of the PDE limits. Gallium ［68Ga］ radionuclide purity is more than 99.9%, other γ nuclide impurities are not detected at the first detection. 24 hours later, germanium ［68Ge］ breakthrough and other γ nuclide impurity content is 0.000 19%±0.000 05% (n=3). The results show that the established analytical methods can accurately determine the impurity of gallium-［68Ga］ chloride solution and effectively control its quality. The impurity content is lower than the limit required by European Pharmacopoeia (EP10.0). The successfully established detection method for impurities of gallium-［68Ga］ chloride solution provides a reference for the impurity control of medical radionuclides and the establishment of quality standards.

间碘苄胍(MIBG)是放射性标记间碘(123I或131I)苄胍的化学前体,为控制MIBG的质量,本研究对自制MIBG进行红外鉴别,测定溶解度、酸碱度、熔点和干燥失重等理化指标,采用ICP-MS法测定元素杂质含量,建立顶空气相色谱法测定残留溶剂无水乙醇,以及HPLC测定MIBG含量和有关物质的方法.多批次分析结果表明,自制MIBG符合人用药前体的要求,与对照品的红外图谱一致,pH在4.0～6.0范围内,熔点为167～170℃,干燥失重＜3％,乙醇残留＜0.5％,元素杂质含量低于控制阈值,MIGB有关物质未检出,MIBG含量在98.0％～102.0％范围内.本研究建立了MIBG的质量标准,可为MIBG的质量控制提供依据.

目的 制备特异性生长抑素受体拮抗剂68Ga-NODAGA-JR11,探讨其用于神经内分泌肿瘤PET显像的可行性.方法 本研究合成了生长抑素受体拮抗剂NODAGA-JR11,并采用比利时IRE公司药用级68Ge/68Ga发生器获得高比活度的68GaCl3溶液进行了68Ga-NODAGA-JR11的制备.结果 经过多次的放射性标记实验(n≥15),得到的标记物68Ga-NODAGA-JR11放化纯均可以保持在95％以上,制备工艺稳定可靠、重现性高.结论 68Ga-NODAGA-JR11具有良好的水溶性和良好的体外稳定性,在荷AR42J肿瘤鼠的micro-PET/CT显像中显示了良好的SSTR靶向性和特异性.68Ga标记的NODAGA-JR11冻干药盒的初步研究及标记表明,所制备的NODAGA-JR11冻干药盒可用于68Ga的标记.

放射性核素标记的生长抑素类似物可与神经内分泌肿瘤(NETs)细胞表面的生长抑素受体(SSTR)特异性结合,因此可用作NETs显像或治疗的靶点.本研究通过双功能螯合剂1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)螯合Al18 F复合物设计合成了一种新型靶向SSTR的放射性探针[Al18 F]NOTA-GABA-KE108.[Al18 F]NOTA-GABA-KE108的合成时间为30 min左右,标记率为60％ ～80％(未校正),经Sep-pak C-18 light柱纯化后,放化纯度>95％.[Al18 F]NOTA-GABA-KE108呈水溶性(lg P=-1.67±0.07),在生理盐水及小牛血清中孵育2 h后放化纯度>95％.在SSTR阳性AR42J和BON1肿瘤细胞中,[Al18 F]NOTA-GABA-KE108探针与受体结合的亲和力(Kd)分别为(1.34±0.60)、(1.45±0.51)μmol/L,且能被特异性抑制,展现出较高的SSTR靶向能力.[Al18 F]NOTA-GABA-KE108在正常KM小鼠肝脏和肾脏中具有高放射性聚集,说明探针主要通过肝肾代谢,在SSTR表达较高的肾上腺和胰腺中有较高的放射性浓集,在BON1荷瘤鼠体内也具有相同的代谢途径,且在血液和肌肉中的本底低,而在肿瘤部位有较高的放射性摄取,具有高的靶与非靶比.以上结果为进一步研究Al18 F复合物标记的生长抑素类似物作为生长抑素受体阳性肿瘤显像剂提供了实验依据.

BackgroundRadionuclide labeled somatostatin analogs can specifically bind to somatostatin receptors (SSTRs) on the cell surface of neuroendocrine tumors (NETs), hence be used for imaging or treatment of NETs.PurposeThis study aims to label glycosylated KE108 protein with 18F nuclide, and to investigate the distributions and PET imaging of this probe in mice in vivo.MethodsA novel 18F-radiolabeled somatostatin analogue probe Gluc-Lys([Al18F]NOTA)-KE108 was designed and synthesized, which linked 18F nuclide and glycosylated KE108 protein by coupling bifunctional chelator (NOTA) to target SSTR positive tumors. The in vitro physicochemical properties, in vitro cell binding, ex vivo biodistribution and in vivo imaging of Gluc-Lys([Al18F]NOTA)-KE108 were further investigated to evaluate the SSTR targeting ability and feasibility of PET imaging in the diagnosis of NETs.ResultsThe efficiency of Gluc-Lys([Al18F]NOTA)-KE108 obtained with moderate labelling is (30±5)% without corrected (n=6), and the radiochemical purity is higher than >95%. The radiochemical yield is ((20±5)%, uncorrected) (n=6), and the total synthesis time is about 20 min. The specific activity is more than 1.37 GBq∙μmol-1. The probe shows expected nanomolar binding affinity in SSTR-positive AR42J and BON1 tumor cells, which Kd values are (152.3±49.1) nmol∙L-1 and (45.5±13.6) nmol∙L-1, respectively, and can be specifically inhibited, showing high SSTR targeting ability. In PET imaging of AR42J tumor bearing mice, Gluc-Lys([Al18F]NOTA)-KE108 has a high uptake of radioactivity and a high ratio of tumor to muscle uptake.ConclusionsGluc-Lys([Al18F]NOTA)-KE108 has high hydrophilicity and good stability in vitro, hence be served as a potential imaging agent for SSTR-positive tumors.