64Cu- and 68Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA–Folate

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• 作者：Renáta Farkas ; Klaudia Siwowska ; Simon M. Ametamey ; Roger Schibli ; Nicholas P. van der Meulen ; Cristina Müller
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：June 6, 2016
• 年：2016
• 卷：13
• 期：6
• 页码：1979-1987
• 全文大小：384K
• 年卷期：0
• ISSN：1543-8392

文摘

A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with ⁶⁴Cu and ⁶⁸Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with ⁶⁴Cu and ⁶⁸Ga was carried out at room temperature within 10 min resulting in ⁶⁴Cu-rf42 and ⁶⁸Ga-rf42 with >95% radiochemical purity. ⁶⁴Cu-rf42 and ⁶⁸Ga-rf42 were stable (>95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of ⁶⁴Cu-rf42 and ⁶⁸Ga-rf42 was determined to be >96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to <1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of ⁶⁴Cu-rf42 and ⁶⁸Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43–0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of ⁶⁴Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of ⁶⁴Cu-rf42 and ⁶⁸Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with ⁶⁴Cu-rf42 and a ⁶⁴Cu-labeled DOTA–folate conjugate (cm10) clearly proved the superiority of NODAGA for stable coordination of ⁶⁴Cu. ⁶⁴Cu-cm10 showed high liver uptake, most probably as a consequence of released ⁶⁴Cu²⁺. The data reported in this study clearly proved the promising features of ⁶⁴Cu-rf42, particularly in terms of favorable tumor-to-kidney ratios. The relatively long half-life of ⁶⁴Cu (T_1/2 = 12.7 h) matches well with the enhanced circulation time of the albumin-binding NODAGA–folate, allowing PET imaging at longer time points after injection than is possible when using ⁶⁸Ga (T_1/2 = 68 min).