An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide

Abstract

Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [ 11 C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [ 11 C]TMZ synthesis and reformulation make it difficult for routine production. Herein we report a highly reproducible one-pot radiosynthesis of [ 11 C]TMZ with a radiochemical yield of 17±5% and >97% radiochemical purity.Chemotherapeutic treatment for advanced cancers persists as an area of intense research exploration. Existing treatment options, including surgery, radiation, and chemotherapy, seldom resulted in even one year of median improved survival for aggressive tumors such as malignant glioma. 1,2 Temozolomide (TMZ) is the prodrug to an antineoplastic alkylating agent that has drawn interest among the research community due to growing evidence for its broad range of chemotherapeutic activity in both in vitro and preclinical in vivo studies. TMZ displays activity against tumors which have resistance to other antitumor agents, and shows potential to improve patient survival outcomes when used in conjunction with radiation and anti-angiogenic therapies. 1,3 TMZ was approved for clinical use in the United States in 1999 and has since proven to be effective as an oral treatment for malignant glioma, malignant metastatic melanoma, and other adult central nervous system tumors.TMZ is currently the standard of care for all newly diagnosed glioblastoma. 4 Prior to the development of TMZ, de novo and acquired resistance to available chemotherapeutics, as well as complications from toxicity, prevented any single drug from attaining much more than a modest increase in overall survival rate. 2 In comparison to other chemotherapies, TMZ is well-tolerated by patients and elicits less severe complications due to nonspecific toxicity. Its off-target toxicity is generally considered mild-to-moderate, and side effects are predictable and easily managed in both adult and pediatric patients, usually with the aid of anti-emetics. 2 Patients who receive TMZ treatment also show improved Health-Related Quality-Of-Life (HR-QOL) scores-a

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

“…25 Methyl isocyanate, however, is a poisonous gas and no longer commercially available. As such, alternate routes 27 or less effective alternatives to methyl isocyanate such as Nsuccinimidyl N-methylcarbamate or N-methylcarbamic chloride must be used that reduce the yield of the cyclizations.…”

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas

“…In general, BBB could block 98% small molecule drugs and almost all of the large molecule drugs. Only a small number of hydrophobic drugs with the molecular weight less than 500 Da could pass through the BBB, such as temozolomide [9][10][11]. Although temozolomide could cross the BBB, and is commonly used as a standard chemotherapeutic for GMB, the therapeutic efficacy of temozolomide is still unsatisfactory due to the limited accumulations of drugs in the brain and the low targeting efficiency in glioma sites.…”