Synthesis and positron emission tomography (PET) study of C-11 labeled Gleevec® (imatinib)

Abstract

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Objectives: PET and labeled chemotherapeutic drugs are potentially powerful tools in assessing whether the drug targets the tumor. Imatinib is a highly potent tyrosine kinase inhibitor for treating chronic myeloid leukemia and gastrointestinal stromal cancer. We set out to develop and evaluate [C-11]imatinib as a tool for measuring imatinib pharmacokinetics in the cancer patient. We report here the synthesis of the precursor, nor-imatinib, and [C-11]imatinib by modification of a patent procedure (Kompella et al., 2004; Collins et al., 2003); the development of a new synthetic route to nor-imatinib and; PET studies of [C-11]imatinib pharmacokinetics in the baboon.

Methods: Demethylation of imatinib was attempted with diethyl azodicarboxylate, α-chloroethylchloroformate, vinyl chloroformate, and the literature method(Collins et al., 2003) using 3-chloroperbenzoic acid(m-CPBA) and ferrous(II) sulfate. Nor-imatinib was also synthesized using new a multi-step procedure. [C-11]Imatinib was synthesized from [C-11]methyl iodide and purified by HPLC(Collins et al., 2003). [C-11]Imatinib pharmacokinetics were measured in brain and peripheral organs in the anesthetized baboon using PET. Log P, plasma protein binding(PPB) and unchanged tracer in arterial plasma were measured.

Results: Imatinib was demethylated only by m-CPBA and ferrous sulfate in a 35% yield. Nor-Imatinib was also synthesized from the corresponding amine and acid in a multi-step procedure using commercially available starting materials in an overall yield of 6.8%. [C-11]Imatinib was synthesized in a radiochemical yield=69±12% (n=6), a specific activity of 1.1~1.4Ci/μmol and a radiochemical purity of >98%. Log P was 2.34±0.17 and PPB was 11.4%. [C-11]Imatinib and/or its labeled metabolites were concentrated in baboon gall bladder>>liver>spleen≈kidney>spinal cord. There was negligible brain uptake. 67% of [C-11]imatinib in plasma at 60min was parent tracer.

Conclusions: A new multi-step synthetic route was developed providing a versatile means for preparing nor-imatinib and its derivatives. [C-11]Imatinib was prepared in high yield and purity. PET studies in the baboon show that [C-11]imatinib is promising PET radiotracer for measuring imatinib pharmacokinetics in cancer patients and other chemotherapeutic applications such as anti-fibrosis therapy(Yoshiji et al.,2005). Negligible brain uptake is consistent with its high molecular weight(493.6).

Research Support (if any): Supported by DOE-OBER; A sample of imatinib was obtained from Novartis International AG.

Bio-distribution of [C-11] imatinib