Division of Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany.
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
J Nucl Med. 2015 Jul;56(7):1100-5. doi: 10.2967/jnumed.114.149583. Epub 2015 May 14.
Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, (68)Ga and (18)F stand out because of the ease of radionuclide introduction (e.g., (68)Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the (18)F isotope). The in vivo properties of good manufacturing practice-compliant, newly developed kitlike-producible (18)F-SiFA- and (18)F-SiFAlin- (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard (68)Ga-DOTATATE for high-quality imaging of somatostatin receptor-bearing tumors.
SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried (18)F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20-25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard (68)Ga-DOTATATE.
Synthetically easily accessible (18)F-labeled silicon-fluoride acceptor-modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than (68)Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for (68)Ga-DOTATATE.
The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios although lower than those observed with (68)Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for (18)F-labeled peptides advantageous for routine clinical application.
比较新型试剂盒生产的（18）F-SiFA-和（18）F-SiFAlin-（SiFA = 硅氟化物受体）修饰的 TATE 衍生物与当前临床金标准（68）Ga-DOTATATE 在高质量成像生长抑素受体阳性肿瘤方面的体内特性。
使用基于盒的干燥（18）F 进行 SiFA-和 SiFAlin 衍生的生长抑素类似物的合成和放射性标记，并通过 C18 盒进行纯化（放射性化学产率为 49.8%±5.9%，在 20-25 分钟内），无需进行高效液相色谱纯化。在体外测试示踪剂的亲脂性和在人血清中的稳定性。使用 AR42J 细胞进行竞争性受体结合亲和力研究。在 AR42J 异种移植小鼠模型中通过离体生物分布和体内 PET/CT 成像研究评估最有前途的示踪剂，评估它们的药代动力学特征，并将结果与当前的临床金标准（68）Ga-DOTATATE 进行比较。
开发了合成上易于获得的（18）F 标记的硅氟化物受体修饰的生长抑素类似物。它们对生长抑素受体阳性肿瘤细胞具有高结合亲和力（1.88-14.82 nM）。最有效的化合物在离体生物分布研究中表现出相当的药代动力学特征，甚至在肿瘤标准化摄取值方面略高于（68）Ga-DOTATATE，在体内 PET/CT 成像中也表现出更高的肿瘤摄取水平。非肿瘤组织中的放射性摄取高于（68）Ga-DOTATATE。
新型 SiFA 砌块 SiFAlin 和亲水性辅助剂的引入使修饰的 TATE 肽具有有利的体内生物分布特征，尽管与（68）Ga-DOTATATE 相比，肿瘤与背景的比值较低，但仍能获得高比值。作为进一步的优势，SiFA 方法为（18）F 标记肽提供了试剂盒式标记程序，有利于常规临床应用。
