Synthesis and Preclinical Evaluation of Folate-NOTA-Al18F for PET Imaging of Folate-Receptor-Positive Tumors

Qingshou Chen, Xiangjun Meng, Paul McQuade, Daniel Rubins, Shu An Lin, Zhizhen Zeng, Hyking Haley, Patricia Miller, Dinko González Trotter, Philip S. Low

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33 Scopus citations


Folate-receptor-targeted PET radiotracers can potentially serve as versatile imaging agents for the diagnosis, staging, and prediction of response to therapy of patients with folate-receptor (FR)-expressing cancers. Because current FR-targeted PET reagents can be compromised by complex labeling procedures, low specific activities, poor radiochemical yields, or unwanted accumulation in FR negative tissues, we have undertaken to design an improved folate-PET agent that might be more amenable for clinical development. For this purpose, we have synthesized a folate-NOTA-Al18F radiotracer and examined its properties both in vitro and in vivo. Methods: Radiochemical synthesis of folate-NOTA-Al18F was achieved by incubating 18F- with AlCl3 for 2 min followed by heating in the presence of folate-NOTA for 15 min at 100 °C. Binding of folate-NOTA-Al18F to FR was quantitated in homogenates of KB and Cal51 tumor xenografts in the presence and absence of excess folic acid as a competitor. In vivo imaging was performed on nu/nu mice bearing either FR+ve (KB cell) or FR-ve (A549 cell) tumor xenografts, and specific accumulation of the radiotracer in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folic acid. Image quality of folate-NOTA-Al18F was compared with that of 99mTc-EC20, a clinically established folate-targeted SPECT imaging agent. Results: Total radiochemical synthesis and purification of folate-NOTA-Al18F was completed within 37 min, yielding a specific activity of 68.82 ± 18.5 GBq/μmol, radiochemical yield of 18.6 ± 4.5%, and radiochemical purity of 98.3 ± 2.9%. Analysis of FR binding revealed a Kd of 1.0 nM, and micro-PET imaging together with ex vivo biodistribution analyses demonstrated high FR-mediated uptake in an FR+ tumor and the kidneys. Conclusions: Folate-NOTA-Al18F constitutes an easily prepared FR-targeted PET imaging agent with improved radiopharmaceutical properties and high specificity for folate receptor expressing tumors. Given its improved properties over 99mTc-EC20 (i.e., higher resolution, shorter image acquisition time, etc.), we conclude that folate-NOTA-Al18F constitutes a viable alternative to 99mTc-EC20 for use in identification, diagnosis, and staging of patients with FR-expressing cancers.

Original languageEnglish (US)
Pages (from-to)1520-1527
Number of pages8
JournalMolecular pharmaceutics
Issue number5
StatePublished - May 2 2016


  • AlF-NOTA chelate
  • F-PET imaging
  • cancer imaging
  • folate receptor
  • imaging autoimmune disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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