TY - JOUR
T1 - Folate-PEG-NOTA-Al18F
T2 - A New Folate Based Radiotracer for PET Imaging of Folate Receptor-Positive Tumors
AU - Chen, Qingshou
AU - Meng, Xiangjun
AU - McQuade, Paul
AU - Rubins, Daniel
AU - Lin, Shu An
AU - Zeng, Zhizhen
AU - Haley, Hyking
AU - Miller, Patricia
AU - González Trotter, Dinko
AU - Low, Philip S.
N1 - Funding Information:
This work was supported by a research grant from Endocyte, Inc. Evaluations of compounds by nuclear magnetic resonance were accomplished using the shared resources of the Purdue University Interdepartmental NMR Facility at the Purdue University Center for Cancer Research (PCCR).
Publisher Copyright:
© 2017 American Chemical Society.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/12/4
Y1 - 2017/12/4
N2 - The folate receptor (FR) has been established as a promising target for imaging and therapy of cancer (FR-α), inflammation, and autoimmune diseases (FR-β). Several folate based PET radiotracers have been reported in the literature, but an 18F-labeled folate-PET imaging agent with optimal properties for clinical translation is still lacking. In the present study, we report the design and preclinical evaluation of folate-PEG12-NOTA-Al18F (1), a new folate-PET agent with improved potential for clinical applications. Radiochemical synthesis of 1 was achieved via a one-pot labeling process by heating folate-PEG12-NOTA in the presence of in situ prepared Al18F for 15 min at 105 °C, followed by HPLC purification. Specific binding of 1 to FR was evaluated on homogenates of KB (FR-positive) and A549 (FR-deficient) tumor xenografts in the presence and absence of excess folate. In vivo tumor imaging with folate-PEG12-NOTA-Al18F was compared to imaging with 99mTc-EC20 using nu/nu mice bearing either KB or A549 tumor xenografts. Specific accumulation of 1 in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folate. Radiosynthesis of 1 was accomplished within -35 min, affording pure radiotracer 1 in 8.4 ± 1.3% (decay corrected) radiochemical yield with 100% radiochemical purity after HPLC purification and a specific activity of 35.8 ± 15.3 GBq/mmol. Further in vitro and in vivo examination of 1 demonstrated highly specific FR-mediated uptake in FR+ tumor, with Kd of -0.4 nM (KB), and reduced accumulation in liver. Given its facile preparation and improved properties, the new radiotracer, folate-PEG12-NOTA-Al18F (1), constitutes a promising tool for identification and classification of patients with FR overexpressing cancers.
AB - The folate receptor (FR) has been established as a promising target for imaging and therapy of cancer (FR-α), inflammation, and autoimmune diseases (FR-β). Several folate based PET radiotracers have been reported in the literature, but an 18F-labeled folate-PET imaging agent with optimal properties for clinical translation is still lacking. In the present study, we report the design and preclinical evaluation of folate-PEG12-NOTA-Al18F (1), a new folate-PET agent with improved potential for clinical applications. Radiochemical synthesis of 1 was achieved via a one-pot labeling process by heating folate-PEG12-NOTA in the presence of in situ prepared Al18F for 15 min at 105 °C, followed by HPLC purification. Specific binding of 1 to FR was evaluated on homogenates of KB (FR-positive) and A549 (FR-deficient) tumor xenografts in the presence and absence of excess folate. In vivo tumor imaging with folate-PEG12-NOTA-Al18F was compared to imaging with 99mTc-EC20 using nu/nu mice bearing either KB or A549 tumor xenografts. Specific accumulation of 1 in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folate. Radiosynthesis of 1 was accomplished within -35 min, affording pure radiotracer 1 in 8.4 ± 1.3% (decay corrected) radiochemical yield with 100% radiochemical purity after HPLC purification and a specific activity of 35.8 ± 15.3 GBq/mmol. Further in vitro and in vivo examination of 1 demonstrated highly specific FR-mediated uptake in FR+ tumor, with Kd of -0.4 nM (KB), and reduced accumulation in liver. Given its facile preparation and improved properties, the new radiotracer, folate-PEG12-NOTA-Al18F (1), constitutes a promising tool for identification and classification of patients with FR overexpressing cancers.
KW - AlF-NOTA
KW - F-PET imaging
KW - cancer imaging
KW - folate conjugate
KW - folate receptor
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U2 - 10.1021/acs.molpharmaceut.7b00415
DO - 10.1021/acs.molpharmaceut.7b00415
M3 - Article
C2 - 29028357
AN - SCOPUS:85037648744
VL - 14
SP - 4353
EP - 4361
JO - Molecular pharmaceutics
JF - Molecular pharmaceutics
SN - 1543-8384
IS - 12
ER -