A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

Oum, Yoon Hyeun; Shetty, Dinesh; Yoon, Younghyoun; Liang, Zhongxing; Voll, Ronald J.; Goodman, Mark M.; Shim, Hyunsuk

doi:10.1016/j.bmc.2019.115240

Cited by 6 publications

(10 citation statements)

References 54 publications

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“…Both PET tracers might be useful in identifying patients to whom potential CXCR4-targeted radiotherapies (e.g., 177 Lu-CXCR4-ligands) could be beneficial [9,10]. Other CXCR4ligands for PET and SPECT have also been reported for the detection of CXCR4 expression in different tumors, but only at a preclinical stage [11][12][13][14]. 68 Ga-Pentixafor ® is the only CXCR4-ligand used in clinical protocols.…”

Section: Introductionmentioning

confidence: 99%

^99mTc-CXCR4-L for Imaging of the Chemokine-4 Receptor Associated with Brain Tumor Invasiveness: Biokinetics, Radiation Dosimetry, and Proof of Concept in Humans

Vallejo-Armenta

Santos-Cuevas

Soto-Andonaegui

et al. 2020

Contrast Media & Molecular Imaging

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Overexpression of the chemokine-4 receptor (CXCR4) in brain tumors is associated with high cancer cell invasiveness. Recently, we reported the preclinical evaluation of 99mTc-CXCR4-L (cyclo-D-Tyr-D-[NMe]Orn[EDDA-99mTc-6-hydrazinylnicotinyl]-Arg-NaI-Gly) as a SPECT radioligand capable of specifically detecting the CXCR4 protein. This research aimed to estimate the biokinetic behavior and radiation dosimetry of 99mTc-CXCR4-L in healthy subjects, as well as to correlate the radiotracer uptake by brain tumors in patients, with the histological grade of differentiation and CXCR4 expression evaluated by immunohistochemistry. 99mTc-CXCR4-L was obtained from freeze-dried kits prepared under GMP conditions (radiochemical purities >97%). Whole-body scans from six healthy volunteers were acquired at 0.3, 1, 2, 4, 6, and 24 h after 99mTc-CXCR4-L administration (0.37 GBq). Time-activity curves of different source organs were obtained from the image sequence to adjust the biokinetic models. The OLINDA/EXM code was employed to calculate the equivalent and effective radiation doses. Nine patients with evidence of brain tumor injury (6 primaries and 3 recurrent), determined by MRI, underwent cerebral SPECT at 3 h after administration of 99mTc-CXCR4-L (0.74 GBq). Data were expressed as a T/B (tumor uptake/background) ratio. Biopsy examinations included histological grading and anti-CXCR4 immunohistochemistry. Results showed a fast blood activity clearance (T1/2α = 0.81 min and T1/2β = 12.19 min) with renal and hepatobiliary elimination. The average equivalent doses were 6.10E − 04, 1.41E − 04, and 3.13E − 05 mSv/MBq for the intestine, liver, and kidney, respectively. The effective dose was 3.92E − 03 mSv/MBq. SPECT was positive in 7/9 patients diagnosed as grade II oligodendroglioma (two patients), grade IV glioblastoma (two patients), grade IV gliosarcoma (one patient), metastasis, and diffuse astrocytoma with T/B ratios of 1.3, 2.3, 13, 7, 19, 5.5, and 3.9, respectively, all of them with positive immunohistochemistry. A direct relationship between the grade of differentiation and the expression of CXCR4 was found. The two negative SPECT studies showed negative immunohistochemistry with a diagnosis of reactive gliosis. This “proof-of-concept” research warrants further clinical studies to establish the usefulness of 99mTc-CXCR4-L in the diagnosis and prognosis of brain tumors.

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Section: Introductionmentioning

confidence: 99%

^99mTc-CXCR4-L for Imaging of the Chemokine-4 Receptor Associated with Brain Tumor Invasiveness: Biokinetics, Radiation Dosimetry, and Proof of Concept in Humans

Vallejo-Armenta

Santos-Cuevas

Soto-Andonaegui

et al. 2020

Contrast Media & Molecular Imaging

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“…This, and the finding that plaque regression was accompanied by a loss of CXCR4 on aortic endothelium, led to the conclusion that high CXCR4 expression on plaque ECs may serve as a molecular marker for endothelial vulnerability/injury [68]. Two other very recent preclinical studies using a small-molecule tracer (entry 6, Table 1) and N-[ 11 C]methyl-AMD3465 as PET imaging agents further highlight the relevance of CXCR4 as a target for immune cell imaging [74,88]. In a model of carrageenaninduced inflammation, significantly higher accumulation of the benzenesulfonamide ligand [ 18 F]5 was observed in the paw edema lesion as compared to the control paw, indicative of the inflammation-induced infiltration with CXCR4-positive immune cells [74].…”

Section: Imaging Of Cxcr4-positive Immune Cells In Preclinical Modelsmentioning

confidence: 98%

“…Two other very recent preclinical studies using a small-molecule tracer (entry 6, Table 1 ) and N-[ 11 C]methyl-AMD3465 as PET imaging agents further highlight the relevance of CXCR4 as a target for immune cell imaging [ 74 , 88 ]. In a model of carrageenan-induced inflammation, significantly higher accumulation of the benzenesulfonamide ligand [ 18 F]5 was observed in the paw edema lesion as compared to the control paw, indicative of the inflammation-induced infiltration with CXCR4-positive immune cells [ 74 ]. In the context of immuno-oncology, an accurate assessment of tumor immune cell infiltration as a response to immunomodulatory cancer treatments is of pivotal importance.…”

Section: Imaging Of Cxcr4-positive Immune Cells In Preclinical Modelsmentioning

confidence: 99%

In Vivo Targeting of CXCR4—New Horizons

Schottelius

Herrmann

Lapa

2021

Cancers

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Given its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) has attracted a lot of interest in the field of nuclear oncology, and clinical evidence on the high potential of CXCR4-targeted theranostics is constantly accumulating. Additionally, since CXCR4 also represents a key player in the orchestration of inflammatory responses to inflammatory stimuli, based on its expression on a variety of pro- and anti-inflammatory immune cells (e.g., macrophages and T-cells), CXCR4-targeted inflammation imaging has recently gained considerable attention. Therefore, after briefly summarizing the current clinical status quo of CXCR4-targeted theranostics in cancer, this review primarily focuses on imaging of a broad spectrum of inflammatory diseases via the quantification of tissue infiltration with CXCR4-expressing immune cells. An up-to-date overview of the ongoing preclinical and clinical efforts to visualize inflammation and its resolution over time is provided, and the predictive value of the CXCR4-associated imaging signal for disease outcome is discussed. Since the sensitivity and specificity of CXCR4-targeted immune cell imaging greatly relies on the availability of suitable, tailored imaging probes, recent developments in the field of CXCR4-targeted imaging agents for various applications are also addressed.

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“…A very recent effort by Oum et al, resulted in a small molecular CXCR4 targeted 18 F-labeled benzenesulfonamide derivative (29, Figure 13). It was synthesized through a nucleophilic substitution reaction using 18 F-fluoride and the corresponding mesylate precursor [135]. Though multiple studies are required, this radiotracer was shown to have potential in tumor imaging and displayed good uptake in human tumor xenografts, metastatic lung tumor tissue of mice, and inflammatory lesions.…”

Section: Cxcr4 Receptor and Pet Tracermentioning

confidence: 99%

PET Imaging Radiotracers of Chemokine Receptors

2021

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Chemokines and chemokine receptors have been recognized as critical signal components that maintain the physiological functions of various cells, particularly the immune cells. The signals of chemokines/chemokine receptors guide various leukocytes to respond to inflammatory reactions and infectious agents. Many chemokine receptors play supportive roles in the differentiation, proliferation, angiogenesis, and metastasis of diverse tumor cells. In addition, the signaling functions of a few chemokine receptors are associated with cardiac, pulmonary, and brain disorders. Over the years, numerous promising molecules ranging from small molecules to short peptides and antibodies have been developed to study the role of chemokine receptors in healthy states and diseased states. These drug-like candidates are in turn exploited as radiolabeled probes for the imaging of chemokine receptors using noninvasive in vivo imaging, such as positron emission tomography (PET). Recent advances in the development of radiotracers for various chemokine receptors, particularly of CXCR4, CCR2, and CCR5, shed new light on chemokine-related cancer and cardiovascular research and the subsequent drug development. Here, we present the recent progress in PET radiotracer development for imaging of various chemokine receptors.

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A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

Cited by 6 publications

References 54 publications

^99mTc-CXCR4-L for Imaging of the Chemokine-4 Receptor Associated with Brain Tumor Invasiveness: Biokinetics, Radiation Dosimetry, and Proof of Concept in Humans

^99mTc-CXCR4-L for Imaging of the Chemokine-4 Receptor Associated with Brain Tumor Invasiveness: Biokinetics, Radiation Dosimetry, and Proof of Concept in Humans

In Vivo Targeting of CXCR4—New Horizons

PET Imaging Radiotracers of Chemokine Receptors

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