title: Synthesis and Preclinical Evaluation of Folate-NOTA-Al(18)F for PET Imaging of Folate-Receptor-Positive Tumors.
abstract: 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-Al(18)F radiotracer and examined its properties both in vitro and in vivo.
  
  
  
  Radiochemical synthesis of folate-NOTA-Al(18)F was achieved by incubating (18)F(-) with AlCl3 for 2 min followed by heating in the presence of folate-NOTA for 15 min at 100 °C. Binding of folate-NOTA-Al(18)F 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-Al(18)F was compared with that of (99m)Tc-EC20, a clinically established folate-targeted SPECT imaging agent.
  
  
  
  Total radiochemical synthesis and purification of folate-NOTA-Al(18)F 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.
  
  
  
  Folate-NOTA-Al(18)F 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 (99m)Tc-EC20 (i.e., higher resolution, shorter image acquisition time, etc.), we conclude that folate-NOTA-Al(18)F constitutes a viable alternative to (99m)Tc-EC20 for use in identification, diagnosis, and staging of patients with FR-expressing cancers.
authors.affiliation: Department of Chemistry, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Qingshou
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Meng
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: McQuade
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rubins
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Shu-An
authors.initials: SA
authors.lastname: Lin
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Hyking
authors.initials: H
authors.lastname: Haley
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miller
authors.affiliation: Imaging, Merck Research Laboratories, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Dinko
authors.initials: D
authors.lastname: González Trotter
authors.affiliation: Department of Chemistry, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
mesh_terms: D000072283:A549 Cells; D000818:Animals; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000008:administration & dosage* / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011854:Radiochemistry / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D005462:Fluorine Radioisotopes; D058973:Folate Receptors, GPI-Anchored; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D005492:Folic Acid
keywords: 18F-PET imaging; Al18F-NOTA chelate; cancer imaging; folate receptor; imaging autoimmune disease