TY - JOUR
T1 - Development and Evaluation of an 18F-Radiolabeled Monocyclam Derivative for Imaging CXCR4 Expression
AU - Brickute, Diana
AU - Braga, Marta
AU - Kaliszczak, Maciej A.
AU - Barnes, Chris
AU - Lau, Doreen
AU - Carroll, Laurence
AU - Stevens, Elizabeth
AU - Trousil, Sebastian
AU - Alam, Israt S.
AU - Nguyen, Quang Dé
AU - Aboagye, Eric O.
N1 - Funding Information:
This work was funded by the Cancer Research UK-Engineering and Physical Sciences Research Council [in association with the Medical Research Council and Department of Health (England)] grant C2536/A10337 and the Cancer Research UK grant C2536/A16584. E.O.A. acknowledges support from the Imperial College NIHR Biomedical Research Centre award (WSCC_P62585), the Medical Research Council grant (MC-A652-5PY80), and the Experimental Cancer Medicine Centres grant (C37/A7283). We thank Dr. Louis Allott for all his help and support throughout the writing of this manuscript.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/5/6
Y1 - 2019/5/6
N2 - In humans, C-X-C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4-CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation for detection and treatment of the disease. Peptidic antagonists have been labeled with a variety of radioisotopes for the detection of CXCR4, but the methodology utilizing small molecules has predominantly used radiometals. We report here the development of a 18F-radiolabeled cyclam-based small molecule radioprobe, [18F]MCFB, for imaging CXCR4 expression. The IC50 value of [19F]MCFB for CXCR4 was similar to that of AMD3465 (111.3 and 89.8 nM, respectively). In vitro binding assays show that the tracer depicted a differential CXCR4 expression, which was blocked in the presence of AMD3465, demonstrating the specificity of [18F]MCFB. Positron emission tomography (PET) imaging studies showed a distinct uptake of the radioprobe in lymphoma and breast cancer xenografts. High liver and kidney uptakes were seen with [18F]MCFB, leading us to further examine the basis of its pharmacokinetics in relation to the tracer's cationic nature and thus the role of organic cation transporters (OCTs). Substrate competition following the intravenous injection of metformin led to a marked decrease in the urinary excretion of [18F]MCFB, with moderate changes observed in other organs, including the liver. Our results suggest involvement of OCTs in the renal elimination of the tracer. In conclusion, the 18F-radiolabeled monocyclam, [18F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.
AB - In humans, C-X-C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4-CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation for detection and treatment of the disease. Peptidic antagonists have been labeled with a variety of radioisotopes for the detection of CXCR4, but the methodology utilizing small molecules has predominantly used radiometals. We report here the development of a 18F-radiolabeled cyclam-based small molecule radioprobe, [18F]MCFB, for imaging CXCR4 expression. The IC50 value of [19F]MCFB for CXCR4 was similar to that of AMD3465 (111.3 and 89.8 nM, respectively). In vitro binding assays show that the tracer depicted a differential CXCR4 expression, which was blocked in the presence of AMD3465, demonstrating the specificity of [18F]MCFB. Positron emission tomography (PET) imaging studies showed a distinct uptake of the radioprobe in lymphoma and breast cancer xenografts. High liver and kidney uptakes were seen with [18F]MCFB, leading us to further examine the basis of its pharmacokinetics in relation to the tracer's cationic nature and thus the role of organic cation transporters (OCTs). Substrate competition following the intravenous injection of metformin led to a marked decrease in the urinary excretion of [18F]MCFB, with moderate changes observed in other organs, including the liver. Our results suggest involvement of OCTs in the renal elimination of the tracer. In conclusion, the 18F-radiolabeled monocyclam, [18F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.
KW - AMD3465
KW - CXCR4
KW - [F]MCFB
KW - cyclam
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U2 - 10.1021/acs.molpharmaceut.9b00069
DO - 10.1021/acs.molpharmaceut.9b00069
M3 - Article
C2 - 30883140
AN - SCOPUS:85065442903
SN - 1543-8384
VL - 16
SP - 2106
EP - 2117
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 5
ER -