Copper-64 is an attractive radionuclide for PET imaging and is frequently used in clinical applications. The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of ⁶⁴Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7-acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH₂), a somatostatin receptor 2 antagonist, with the clinically used sst2 agonist ⁶⁴Cu-DOTA-TATE ((TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated K_d values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist ^64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist ^64/natCu-DOTA-TATE. Cell uptake studies showed the expected differences between agonists and antagonists. Whereas ⁶⁴Cu-DOTA-TATE (the agonist) showed very effective internalization in the cell culture assay (with 50% internalized at 4 hours post-peptide addition under the given experimental conditions), ⁶⁴Cu-NODAGA-JR11 (the antagonist) showed little internalization but strong receptor-mediated uptake at the cell membrane. Biodistribution studies of ⁶⁴Cu-NODAGA-JR11 showed rapid blood clearance and tumor uptake with increasing tumor-to-relevant organ ratios within the first 4 hours and in some cases, 24 hours, respectively. The tumor washout was slow or non-existent in the first 4 hours, whereas the kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Specificity of tumor uptake was proven by co-injection of high excess of non-radiolabeled peptide, which led to >80% tumor blocking. ⁶⁴Cu-DOTA-TATE showed less favorable pharmacokinetics, with the exception of lower kidney uptake. Blood clearance was distinctly slower and persistent higher blood values were found at 24 hours. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of ⁶⁴Cu-NODAGA-JR11 at 1 h, but release from the tumor was very fast, particularly between 4 and 24 hours. Tumor-to-normal organ ratios were distinctly lower after 1 hour. This is indicative of insufficient in vivo stability. PET studies of ⁶⁴Cu-NODAGA-JR11 reflected the biodistribution data with nicely delineated tumor and low background. ⁶⁴Cu-NODAGA-JR11 shows promising pharmacokinetic properties for further translation into the clinic.

Copper-64 是一种对 PET 成像有吸引力的放射性核素，经常用于临床应用。本研究的目的是对⁶⁴ Cu-NODAGA-JR11 (NODAGA = 1,4,7-三氮杂环壬烷,1-戊二酸,4,7-乙酸，JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH ₂ )，生长抑素受体 2 拮抗剂，具有临床使用的 sst2 激动剂⁶⁴ Cu-DOTA-TATE ((TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr)。体外研究表明 K _d值为 5.7±0.95 nM拮抗剂^64/nat Cu-NODAGA-JR11 的 Bmax = 4.1±0.18 nM，激动剂^64/nat Cu-DOTA-TATE 的 Bmax = 0.48±0.18 nM。激动剂和拮抗剂之间存在预期差异，而⁶⁴ Cu-DOTA-TATE（激动剂）在细胞培养测定中显示出非常有效的内化（在给定实验条件下，肽添加后 4 小时内内化 50%），而⁶⁴ Cu-NODAGA 则显示出非常有效的内化。 -JR11（拮抗剂）几乎没有表现出内化作用，但细胞膜上的受体介导的摄取很强。 64 Cu-NODAGA-JR11 的生物分布研究表明，在最初 4 小时内，在某些情况下，24 小时内，随着肿瘤与相关器官比率的增加， ⁶⁴ Cu-NODAGA-JR11 迅速被血液清除和肿瘤摄取。在前 4 小时内，肿瘤清除缓慢或根本不存在，而肾脏清除非常有效，导致肿瘤与肾脏的比率随着时间的推移而升高并不断增加。 通过共注射高过量的非放射性标记肽证明了肿瘤摄取的特异性，这导致 >80% 的肿瘤阻断。 ⁶⁴ Cu-DOTA-TATE 显示出较差的药代动力学，但肾脏摄取较低。血液清除速度明显减慢，24 小时后血液数值持续升高。肝脏和肺的吸收相对较高且持续。肿瘤摄取具有特异性，并且与⁶⁴ Cu-NODAGA-JR11 在 1 小时内的摄取相似，但从肿瘤中的释放非常快，特别是在 4 至 24 小时之间。 1小时后肿瘤与正常器官的比率明显降低。这表明体内稳定性不足。 ⁶⁴ Cu-NODAGA-JR11 的 PET 研究反映了生物分布数据，肿瘤轮廓清晰且背景低。 ⁶⁴ Cu-NODAGA-JR11 显示出有希望进一步转化为临床的药代动力学特性。