Radiosynthesis and preclinical evaluation of [68Ga]Ga-NOTA-folate for PET imaging of folate receptor β-positive macrophages

Authors: Olli Moisio, Senthil Palani, Jenni Virta, Petri Elo, Heidi Liljenbäck, Tuula Tolvanen, Meeri Käkelä, Maxwell G. Miner, Erika Atencio Herre, Päivi Marjamäki, Tiit Örd, Merja Heinäniemi, Minna U. Kaikkonen, Fenghua Zhang, Madduri Srinivasarao, Juhani Knuuti, Philip S. Low, Antti Saraste, Xiang-Guo Li, Anne Roivainen

Journal: Scientific Reports

Year: 2020

DOI: https://doi.org/10.1038/s41598-020-70394-3

Abstract

Abstract Folate receptor β (FR-β), a marker expressed on macrophages, is a promising target for imaging of inflammation. Here, we report the radiosynthesis and preclinical evaluation of [ 68 Ga]Ga-NOTA-folate ( 68 Ga-FOL). After determining the affinity of 68 Ga-FOL using cells expressing FR-β, we studied atherosclerotic mice with 68 Ga-FOL and 18 F-FDG PET/CT. In addition, we studied tracer distribution and co-localization with macrophages in aorta cryosections using autoradiography, histology, and immunostaining. The specificity of 68 Ga-FOL was assessed in a blocking study with folate glucosamine. As a final step, human radiation doses were extrapolated from rat PET data. We were able to produce 68 Ga-FOL with high radiochemical purity and moderate molar activity. Cell binding studies revealed that 68 Ga-FOL had 5.1 nM affinity for FR-β. Myocardial uptake of 68 Ga-FOL was 20-fold lower than that of 18 F-FDG. Autoradiography and immunohistochemistry of the aorta revealed that 68 Ga-FOL radioactivity co-localized with Mac-3–positive macrophage-rich atherosclerotic plaques. The plaque-to-healthy vessel wall ratio of 68 Ga-FOL was significantly higher than that of 18 F-FDG. Blocking studies verified that 68 Ga-FOL was specific for FR. Based on estimations from rat data, the human effective dose was 0.0105 mSv/MBq. Together, these findings show that 68 Ga-FOL represents a promising new FR-β–targeted tracer for imaging macrophage-associated inflammation.