Synthesis and Evaluation of a Novel 64Cu- and 67Ga-Labeled Neurokinin 1 Receptor Antagonist for in Vivo Targeting of NK1R-Positive Tumor Xenografts,Bioconjugate Chemistry

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Synthesis and Evaluation of a Novel 64Cu- and 67Ga-Labeled Neurokinin 1 Receptor Antagonist for in Vivo Targeting of NK1R-Positive Tumor Xenografts
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-02-21 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00063
Hanwen Zhang ₁ , Ananda Kumar Kanduluru ₂ , Pooja Desai ₁ , Afruja Ahad ₁ , Sean Carlin ₁ , Nidhi Tandon ₁ , Wolfgang A. Weber _{1,

3} , Philip S. Low ₂

Affiliation

Neurokinin 1 receptor (NK1R) is expressed in gliomas and neuroendocrine malignancies and represents a promising target for molecular imaging and targeted radionuclide therapy. The goal of this study was to synthesize and evaluate a novel NK1R ligand (NK1R-NOTA) for targeting NK1R-expressing tumors. Using a carboxymethyl moiety linked to L-733060 as a starting reagent, NK1R-NOTA was synthesized in a three-step reaction and then labeled with ⁶⁴Cu (or ⁶⁷Ga for in vitro studies) in the presence of CH₃COONH₄ buffer. The radioligand affinity and cellular uptake were evaluated with NK1R-transduced HEK293 cells (HEK293-NK1R) and NK1R nontransduced HEK293 cells (HEK293-WT) and their xenografts. Radiolabeled NK1R-NOTA was obtained with a radiochemical purity of >95% and specific activities of >7.0 GBq/μmol for ⁶⁴Cu and >5.0 GBq/μmol for ⁶⁷Ga. Both ⁶⁴Cu- and ⁶⁷Ga-labeled NK1R-NOTA demonstrated high levels of uptake in HEK293-NK1R cells, whereas co-incubation with an excess of NK1R ligand L-733060 reduced the level of uptake by 90%. Positron emission tomography (PET) imaging showed that [⁶⁴Cu]NK1R-NOTA had a accumulated rapidly in HEK293-NK1R xenografts and a 10-fold lower level of uptake in HEK293-WT xenografts. Radioactivity was cleared by gastrointestinal tract and urinary systems. Biodistribution studies confirmed that the tumor-to-organ ratios were ≥5 for all studied organs at 1 h p.i., except kidneys, liver, and intestine, and that the tumor-to-intestine and tumor-to-kidney ratios were also improved 4 and 20 h post-injection. [⁶⁴Cu]NK1R-NOTA is a promising ligand for PET imaging of NK1R-expressing tumor xenografts. Delayed imaging with [⁶⁴Cu]NK1R-NOTA improves image contrast because of the continuous clearance of radioactivity from normal organs.

中文翻译：

合成和一种新型的评价⁶⁴ CU-和⁶⁷ Ga-标记的神经激肽1受体拮抗剂在体内NK1R阳性肿瘤异种移植物的定位

神经激肽1受体（NK1R）在神经胶质瘤和神经内分泌恶性肿瘤中表达，代表了分子成像和靶向放射性核素治疗的有希望的靶标。这项研究的目的是合成和评估一种新型的NK1R配体（NK1R-NOTA），用于靶向表达NK1R的肿瘤。使用连接到L-733060的羧甲基部分作为起始试剂，通过三步反应合成NK1R-NOTA，然后在存在CH ₃ COONH ₄的情况下用⁶⁴ Cu（或⁶⁷ Ga用于体外研究）标记缓冲。用NK1R转导的HEK293细胞（HEK293-NK1R）和NK1R非转导的HEK293细胞（HEK293-WT）及其异种移植物评估了放射性配体的亲和力和细胞摄取。放射性标记的NK1R-NOTA用的> 95％放射化学纯度和> 7.0吉贝/微摩尔的特定活动得到⁶⁴ Cu和> 5.0吉贝/微摩尔为⁶⁷镓，两个⁶⁴ CU-和⁶⁷ Ga-标记的NK1R-NOTA证明高在HEK293-NK1R细胞中的摄取水平降低，而与过量的NK1R配体L-733060共同孵育使摄取水平降低了90％。正电子发射断层扫描（PET）成像显示[ ⁶⁴Cu] NK1R-NOTA在HEK293-NK1R异种移植物中迅速积累，在HEK293-WT异种移植物中的摄取水平低10倍。胃肠道和泌尿系统清除了放射性。生物分布研究证实，除了肾脏，肝脏和肠道外，所有研究的器官在pi 1 h时的肿瘤器官比率均≥5，并且肿瘤肠和肾肾脏比率也得到了改善4注射后20小时。[ ⁶⁴ Cu] NK1R-NOTA是表达NK1R的肿瘤异种移植物的PET成像的有前途的配体。由于[ ⁶⁴ Cu] NK1R-NOTA的放射能从正常器官中连续清除，因此延迟成像可以改善图像对比度。

更新日期：2018-02-21

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