Development and Evaluation of an ¹⁸F-Radiolabeled Monocyclam Derivative for Imaging CXCR4 Expression

Abstract

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.

C-terminal–modified LY2510924: a versatile scaffold for targeting C-X-C chemokine receptor type 4

“…Considering significantly higher binding affinity of Ga-FRM001 to CXCR4 than to AMD3100, the hepatic accumulation of 67 Ga-FRM001 would be attributable to another yet-unknown mechanism, as also reported in other CXCR4-targeting probes 7,31,55 . Recently, the involvement of organic cation transporters has been discussed as a hepatic accumulation mechanism 56 . The blockage of hepatic accumulation of 67 Ga-FRM001 by AMD3100 co-injection would facilitate the renal excretion of free 67 Ga-FRM001 in plasma, which was reflected in a slight but significant increase in the renal radioactivity levels (Table 2).…”

The biological role of the CXCL12/CXCR4 axis in esophageal squamous cell carcinoma

“…In addition, AMD3100 has been labeled with copper 64 to visualize CXCR4-positive tumor cells in vivo and can be used to guide and monitor anti-CXCR4 tumor treatment 113 . Several other agents, such as CXCL12-based imaging agent and bioluminescence, have been developed for tumor diagnostic imaging [114][115][116] .…”

PET Imaging Radiotracers of Chemokine Receptors

“…More studies might be required to improve the utility of these tracers as CXCR4 imaging agents in tumors [133]. Considering the limitations of previous 18 F-labeled cyclam derivatives, Brickute et al, in 2019 described a metabolically stable 18 F-labeled radiotracer ([ 18 F]MCFB, 28, Figure 13) based on AMD-3465, wherein they replaced 2-pyridylmethylamine of AMD-3465 with 1-aminomethyl-4-fluorobenzene [134]. The radiosynthesis of 28 was accomplished via reductive amination using 4-[ 18 F]fluorobenzaldehyde and the corresponding primary amine precursor with a modest MA of 5.7 GBq/µmol.…”