Dataset Information

Al[18F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression.

ABSTRACT: PURPOSE:Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F-18 labeling route of T140, a CXCR4 peptide-based antagonist. PROCEDURES:T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[(18)F]. Al[(18)F]NOTA-T140 was evaluated in vitro in cell-based assay and stability in mouse serum and in vivo using CXCR4 positive and negative tumor xenograft models. RESULTS:Labeling of Al[(18)F]NOTA-T140 was completed within 30 min with a radiochemical yield of 58?±?5.3 % at the end of synthesis, based on fluoride-18 activity. Al[(18)F]NOTA-T140 accumulated in CHO-CXCR4 positive but not negative tumors. Al[(18)F]NOTA-T140 uptake in the tumors correlated with CXCR4 protein expression. Moreover, Al[(18)F]NOTA-T140 had high accumulation in CXCR4-positive metastatic tumors. CONCLUSIONS:The simplicity of Al[(18)F]NOTA-T140 labeling along with its properties to specifically image CXCR4 expression by tumors warrant further clinical application for the diagnosis of CXCR4 clinically.

SUBMITTER: Yan X

PROVIDER: S-EPMC5242338 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Al[18F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression.

Yan Xuefeng X Niu Gang G Wang Zhe Z Yang Xiangyu X Kiesewetter Dale O DO Jacobson Orit O Shen Baozhong B Chen Xiaoyuan X

Molecular imaging and biology 20160201 1

<h4>Purpose</h4>Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F-18 labeling route of T140, a CXCR4 peptide-based antagonist.<h4>Procedures</h4>T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[(18)F]. ...[more]

PMID: 26126597

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Project description:UNLABELLED:Expression of the chemokine receptor CXCR4 by cancers has been shown to correlate with tumor aggressiveness and poor prognosis and may also contribute to metastatic seeding of organs that express its ligand SDF-1. However, fully optimized PET agents for determining CXCR4 expression by tumor cells in vivo are not yet available. This study aims to develop a stable, (18)F-labeled peptide that enables in vivo quantification of CXCR4 in cancer. METHODS:4-F-benzoyl-TN14003 (4-F-T140), a short peptide antagonist of CXCR4 with 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl protecting groups on the ?-amino groups of the lysine residues, was labeled with (18)F-fluoride via N-succinimidyl-4-(18)F-fluorobenzoate conjugation, followed by deprotection to give 4-(18)F-T140 that was exclusively labeled on the ?-amine at the N terminus. Cell binding, migration, biodistribution, and small-animal PET studies of 4-(18)F-T140 were performed. RESULTS:4-F-T140 was radiolabeled by coupling with N-succinimidyl-4-(18)F-fluorobenzoate, with an overall decay-corrected radiochemical yield of 15% ± 5% calculated from the start of synthesis. The mean measured specific activity (±SD) was 7 ± 2 GBq/?mol (0.19 ± 0.05 Ci/?mol), and radiochemical purity was greater than 99%. 4-(18)F-T140 was found to bind specifically to red blood cells in vitro and in vivo. The binding of 4-(18)F-T140 to red blood cells was blocked with a small amount of cold 4-F-T140, which led to higher uptake of 4-(18)F-T140 by Chinese hamster ovarian (CHO)-CXCR4 tumors. Biodistribution experiments at 3 h after injection with the addition of 10 ?g of cold 4-F-T140 showed a 3.03 ± 0.31 percentage injected dose per gram uptake in CHO-CXCR4 tumors, with a tumor-to-blood ratio of 27.1 ± 8.7 and a tumor-to-muscle ratio of 21.6 ± 7.1. PET studies demonstrated clear visualization of CXCR4-transfected, but not CXCR4-negative, CHO tumors. CONCLUSION:4-(18)F-T140 can be used as a PET tracer to image tumor expression of CXCR4, with a high tumor-to-background ratio. The knowledge of whether tumors express or do not express CXCR4 might be beneficial in determining appropriate treatment and monitoring.

Project description:BACKGROUND:Gallium-68 labeled synthetic somatostatin analogs for PET/CT imaging are the current gold standard for somatostatin receptor imaging in neuroendocrine tumor patients. Despite good imaging properties, their use in clinical practice is hampered by the low production levels of 68Ga eluted from a 68Ge/68Ga generator. In contrast, 18F-tracers can be produced in large quantities allowing centralized production and distribution to distant PET centers. [18F]AlF-NOTA-octreotide is a promising tracer that combines a straightforward Al18F-based production procedure with excellent in vivo pharmacokinetics and specific tumor uptake, demonstrated in SSTR2 positive tumor mice. However, advancing towards clinical studies with [18F]AlF-NOTA-octreotide requires the development of an efficient automated GMP production process and additional preclinical studies are necessary to further evaluate the in vivo properties of [18F]AlF-NOTA-octreotide. In this study, we present the automated GMP production of [18F]AlF-NOTA-octreotide on the Trasis AllinOne® radio-synthesizer platform and quality control of the drug product in accordance with GMP. Further, radiometabolite studies were performed and the pharmacokinetics and biodistribution of [18F]AlF-NOTA-octreotide were assessed in healthy rats using μPET/MR. RESULTS:The production process of [18F]AlF-NOTA-octreotide has been validated by three validation production runs and the tracer was obtained with a final batch activity of 10.8 ± 1.3 GBq at end of synthesis with a radiochemical yield of 26.1 ± 3.6% (dc), high radiochemical purity and stability (96.3 ± 0.2% up to 6 h post synthesis) and an apparent molar activity of 160.5 ± 75.3 GBq/μmol. The total synthesis time was 40 ± 3 min. Further, the quality control was successfully implemented using validated analytical procedures. Finally, [18F]AlF-NOTA-octreotide showed high in vivo stability and favorable pharmacokinetics with high and specific accumulation in SSTR2-expressing organs in rats. CONCLUSION:This robust and automated production process provides high batch activity of [18F]AlF-NOTA-octreotide allowing centralized production and shipment of the compound to remote PET centers. Further, the production process and quality control developed for [18F]AlF-NOTA-octreotide is easily implementable in a clinical setting and the tracer is a potential clinical alternative for somatostatin directed 68Ga labeled peptides obviating the need for a 68Ge/68Ga-generator. Finally, the favorable in vivo properties of [18F]AlF-NOTA-octreotide in rats, with high and specific accumulation in SSTR2 expressing organs, supports clinical translation.

Project description:Background:The chemokine receptor 4 (CXCR4) is an important molecular target for both visualization and therapy of tumors. The aim of the present study was the synthesis and preclinical evaluation of a 64Cu-labeled, CXCR4-targeting peptide for positron emission tomography (PET) imaging of CXCR4 expression in vivo. Methods:For this purpose, 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), or 1,4,7-triazacyclononane-triacetic acid (NOTA) was conjugated to the highly affine CXCR4-targeting pentixather scaffold. Affinities were determined using Jurkat T-lymphocytes in competitive binding assays employing [125I]FC131 as the radioligand. Internalization and efflux studies of [64Cu]NOTA-pentixather were performed in chem-1 cells, stably transfected with hCXCR4. The stability of the tracer was evaluated in vitro and in vivo. Small-animal PET and biodistribution studies at different time points were performed in Daudi lymphoma-bearing severe combined immunodeficiency (SCID) mice. Results:[64Cu]NOTA-pentixather was rapidly radiolabeled at 60 °C with high radiochemical yields ?90% and purities >99%. [64Cu]NOTA-pentixather offered the highest affinity of the evaluated peptides in this study (IC50?=?14.9?±?2.1 nM), showed efficient CXCR4-targeting in vitro and was stable in blood and urine with high resistance to transchelation in ethylenediaminetetraacetic acid (EDTA) challenge studies. Due to the enhanced lipophilicity of [64Cu]NOTA-pentixather (logP?=?-1.2), biodistribution studies showed some nonspecific accumulation in the liver and intestines. However, tumor accumulation (13.1?±?1.5% ID/g, 1.5 h p.i.) was CXCR4-specific and higher than in all other organs and resulted in high resolution delineation of Daudi tumors in PET/CT images in vivo. Conclusions:[64Cu]NOTA-pentixather was fast and efficiently radiolabeled, showed effective CXCR4-targeting, high stability in vitro and in vivo and resulted in high resolution PET/CT images accompanied with a suitable biodistribution profile, making [64Cu]NOTA-pentixather a promising tracer for future application in humans.

Dataset Information

Al[18F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression.

Publications

Al[18F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression.

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