title: Synthesis of [3-N-(11) C-methyl]temozolomide via in situ activation of 3-N-hydroxymethyl temozolomide and alkylation with [(11) C]methyl iodide.
abstract: Temozolomide is a chemotherapeutic drug that is mainly used in the treatment of primary glioblastoma multiforme and recurrent high-grade glioma. Here, we report an efficient good manufacturing practice compliant method for the synthesis of [3-N-(11) C-methyl]temozolomide from 3-N-hydroxymethyl temozolomide that cleaves off formaldehyde in situ and becomes activated towards alkylation with [(11) C]methyl iodide. The labelling method was developed for an on-going patient study in which the predictive value of [3-N-(11) C-methyl]temozolomide and positron emission tomography on the outcome of temozolomide treatment is being investigated. The precursor was reacted with [(11) C]methyl iodide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile, heated at stepwise increasing temperature. Purification by semipreparative HPLC with pharmaceutical grade eluent and filtration gave approximately 10 mL sterile product solution ready for injection containing 1.55 ± 0.38 GBq (n = 5), the specific activity was 88 ± 25 GBq/µmol and the radiochemical purity was 98.5 ± 1.9%. (13) C-NMR spectroscopy confirmed the labelled position after colabelling with (11) C and (13) C.
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; PET Centre, Uppsala University Hospital, Uppsala, Sweden; Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.forename: Rolph
authors.initials: R
authors.lastname: Van Kooij
authors.forename: Robert C
authors.initials: RC
authors.lastname: Schuit
authors.forename: Femke E
authors.initials: FE
authors.lastname: Froklage
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Reijneveld
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
mesh_terms: D000478:Alkylation; D002250:Carbon Radioisotopes / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006847:Hydrocarbons, Iodinated / Q000737:chemistry*; D011854:Radiochemistry; D000077204:Temozolomide
chemical_list: D002250:Carbon Radioisotopes; D006847:Hydrocarbons, Iodinated; D003606:Dacarbazine; C014055:methyl iodide; D000077204:Temozolomide
keywords: PET; carbon-11; positron emission tomography; temozolomide