Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas
CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAF V600E ), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2018-09-01
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| Series: | Molecular Imaging |
| Online Access: | https://doi.org/10.1177/1536012118795952 |
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| author | Cuiping Jiang MMSc Lin Xie MD, PhD Yiding Zhang BSc Masayuki Fujinaga PhD Wakana Mori MSc Yusuke Kurihara PhD Tomoteru Yamasaki PhD Feng Wang MD, PhD Ming-Rong Zhang MD, PhD |
| author_facet | Cuiping Jiang MMSc Lin Xie MD, PhD Yiding Zhang BSc Masayuki Fujinaga PhD Wakana Mori MSc Yusuke Kurihara PhD Tomoteru Yamasaki PhD Feng Wang MD, PhD Ming-Rong Zhang MD, PhD |
| author_sort | Cuiping Jiang MMSc |
| collection | DOAJ |
| description | CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAF V600E ), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([ 11 C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [ 11 C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAF V600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [ 11 C]CEP-32496 showed high binding affinity for BRAF V600E -positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAF V600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [ 11 C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [ 11 C]CEP-32496 in plasma. Our results indicate that [ 11 C]CEP-32496 has excellent specificity and affinity for the BRAF V600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further. |
| format | Article |
| id | doaj-art-e32529a157ad4fd59a572ae056412ea7 |
| institution | Kabale University |
| issn | 1536-0121 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Molecular Imaging |
| spelling | doaj-art-e32529a157ad4fd59a572ae056412ea72025-02-03T10:07:51ZengSAGE PublishingMolecular Imaging1536-01212018-09-011710.1177/1536012118795952Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced MelanomasCuiping Jiang MMSc0Lin Xie MD, PhD1Yiding Zhang BSc2Masayuki Fujinaga PhD3Wakana Mori MSc4Yusuke Kurihara PhD5Tomoteru Yamasaki PhD6Feng Wang MD, PhD7Ming-Rong Zhang MD, PhD8 Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, JapanCEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAF V600E ), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([ 11 C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [ 11 C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAF V600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [ 11 C]CEP-32496 showed high binding affinity for BRAF V600E -positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAF V600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [ 11 C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [ 11 C]CEP-32496 in plasma. Our results indicate that [ 11 C]CEP-32496 has excellent specificity and affinity for the BRAF V600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.https://doi.org/10.1177/1536012118795952 |
| spellingShingle | Cuiping Jiang MMSc Lin Xie MD, PhD Yiding Zhang BSc Masayuki Fujinaga PhD Wakana Mori MSc Yusuke Kurihara PhD Tomoteru Yamasaki PhD Feng Wang MD, PhD Ming-Rong Zhang MD, PhD Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas Molecular Imaging |
| title | Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas |
| title_full | Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas |
| title_fullStr | Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas |
| title_full_unstemmed | Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas |
| title_short | Pharmacokinetic Evaluation of [C]CEP-32496 in Nude Mice Bearing BRAF Mutation-Induced Melanomas |
| title_sort | pharmacokinetic evaluation of c cep 32496 in nude mice bearing braf mutation induced melanomas |
| url | https://doi.org/10.1177/1536012118795952 |
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