Development of [11C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts

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Abstract

Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [11C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.

Original languageEnglish
Pages (from-to)38337-38350
Number of pages14
JournalOncotarget
Volume8
Issue number24
DOIs
Publication statusPublished - 13 Jun 2017

Cite this

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title = "Development of [11C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts",
abstract = "Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4{\%} yield (decay corrected, calculated from [11C]CO) in > 99{\%} radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95{\%} intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.",
keywords = "BRAF, Personalized medicine, PET, V600E, Vemurafenib",
author = "Paul Slobbe and Windhorst, {Albert D.} and Kevin Adamzek and Marije Bolijn and Schuit, {Robert C.} and Heideman, {Dani{\"e}lle A.M.} and {van Dongen}, {Guus A.M.S.} and Poot, {Alex J.}",
year = "2017",
month = "6",
day = "13",
doi = "10.18632/oncotarget.16321",
language = "English",
volume = "8",
pages = "38337--38350",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "24",

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TY - JOUR

T1 - Development of [11C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts

AU - Slobbe, Paul

AU - Windhorst, Albert D.

AU - Adamzek, Kevin

AU - Bolijn, Marije

AU - Schuit, Robert C.

AU - Heideman, Daniëlle A.M.

AU - van Dongen, Guus A.M.S.

AU - Poot, Alex J.

PY - 2017/6/13

Y1 - 2017/6/13

N2 - Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [11C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.

AB - Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [11C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.

KW - BRAF

KW - Personalized medicine

KW - PET

KW - V600E

KW - Vemurafenib

UR - http://www.scopus.com/inward/record.url?scp=85020698530&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.16321

DO - 10.18632/oncotarget.16321

M3 - Article

VL - 8

SP - 38337

EP - 38350

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 24

ER -