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Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

Fani, Melpomeni ; Wang, Xuejuan ; Nicolas, Guillaume ; Medina, Christelle ; Raynal, Isabelle ; Port, Marc ; Maecke, Helmut

In: European Journal of Nuclear Medicine and Molecular Imaging, 2011, vol. 38, no. 1, p. 108-119

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    Titre
    • Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates
    Auteur
    • Fani, Melpomeni. Division of Radiological Chemistry, University Hospital Basel, 4031, Basel, Switzerland
    • Wang, Xuejuan. Division of Radiological Chemistry, University Hospital Basel, 4031, Basel, Switzerland
    • Nicolas, Guillaume. Department of Nuclear Medicine, University Hospital Basel, 4031, Basel, Switzerland
    • Medina, Christelle. Research Department, Guerbet, 93600, Aulnay-sous-Bois, France
    • Raynal, Isabelle. Research Department, Guerbet, 93600, Aulnay-sous-Bois, France
    • Port, Marc. Research Department, Guerbet, 93600, Aulnay-sous-Bois, France
    • Maecke, Helmut. Division of Radiological Chemistry, University Hospital Basel, 4031, Basel, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • European Journal of Nuclear Medicine and Molecular Imaging, 2011, vol. 38, no. 1, p. 108-119. Springer-Verlag
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:309545
    Summary
    Purpose: A number of 111In- and 99mTc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68Ga from a generator. The aim of the study was to develop a new 68Ga-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 67/68Ga. 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 111In-DTPA-folate (111In-P3139). Results: The Kd values of 67/68Ga-P3026 (4.65 ± 0.82 nM) and 67/68Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68Ga-P3026 > 67/68Ga-P1254 > 111In-P3139, while almost double cellular retention was found for 67/68Ga-P3026 and 67/68Ga-P1254, compared to 111In-P3139. The biodistribution data of 67/68Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111In-P3139. PET/CT images, performed with 68Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. Conclusion: The DOTA-folate conjugates can be efficiently labelled with 68Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68Ga-DOTA-folates are comparable to 111In-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