title: Development of new folate-based PET radiotracers: preclinical evaluation of ⁶⁸Ga-DOTA-folate conjugates.
abstract: OBJECTIVE
  A number of (111)In- and (99m)Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A (68)Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of (68)Ga from a generator. The aim of the study was to develop a new (68)Ga-folate-based PET radiotracer.
  
  
  METHODS
  Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with (67/68)Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule (111)In-DTPA-folate ((111)In-P3139).
  
  
  RESULTS
  The K(d) values of (67/68)Ga-P3026 (4.65 ± 0.82 nM) and (67/68)Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order (67/68)Ga-P3026 > (67/68)Ga-P1254 > (111)In-P3139, while almost double cellular retention was found for (67/68)Ga-P3026 and (67/68)Ga-P1254, compared to (111)In-P3139. The biodistribution data of (67/68)Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to (111)In-P3139. PET/CT images, performed with (68)Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours.
  
  
  CONCLUSIONS
  The DOTA-folate conjugates can be efficiently labelled with (68)Ga in labelling yields and specific activities which allow clinical application. The characteristics of the (67/68)Ga-DOTA-folates are comparable to (111)In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers for FR-positive tumours.
authors.affiliation: Division of Radiological Chemistry, University Hospital Basel, 4031, Basel, Switzerland.
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Fani
authors.forename: Xuejuan
authors.initials: X
authors.lastname: Wang
authors.forename: Guillaume
authors.initials: G
authors.lastname: Nicolas
authors.forename: Christelle
authors.initials: C
authors.lastname: Medina
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raynal
authors.forename: Marc
authors.initials: M
authors.lastname: Port
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D001692:Biological Transport; D004353:Drug Evaluation, Preclinical; D005260:Female; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D058972:Folic Acid Transporters / Q000378:metabolism; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007624:KB Cells; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D058972:Folic Acid Transporters; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D011849:Radioactive Tracers; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005492:Folic Acid
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