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. 2012 Dec 7;14(23):5872-5.
doi: 10.1021/ol302791x. Epub 2012 Nov 14.

An Efficient and Practical Radiosynthesis of [11C]temozolomide

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Free PMC article

An Efficient and Practical Radiosynthesis of [11C]temozolomide

Christian K Moseley et al. Org Lett. .
Free PMC article

Erratum in

  • Org Lett. 2013 Feb 15;15(4):973

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. A highly reproducible one-pot radiosynthesis of [(11)C]TMZ with a radiochemical yield of 17 ± 5% and ≥97% radiochemical purity is reported.

Figures

Figure 1
Figure 1. 13C-NMR spectra for methylation of norTMZ with [13C]CH3I
13C-NMR spectra (500 MHz, DMF-d7 peaks at 30 and 35 ppm) of (a.) reference standard temozolomide (TMZ, 1); the peak corresponding to 3-N-methyl appears at 36.1 ppm; (b) reaction using > 1.0 equivalent NaH (60% w/w) with 13CH3I at 0 °C, rt = 5 min; primary amide methylation at the 8-N position corresponding to 25.5 ppm (pointed as arrow) was observed; (c) using 1 equivalent NaH (60% w/w) with 13CH3I at 0 °C, rt = 5 min; [3-N-13C-methyl]temozolomide formation at 36.1 ppm and 8-N-methylated product formation at 26.4 (pointed as arrow) were observed; (d) using < 1.0 equivalent NaH (60% w/w) with 13CH3I at 0 °C, rt = 5 min; [3-N-13C-methyl]temozolomide formation at 35.9 ppm was observed. Excess [13C]CH3I observed at −23.5 ppm.
Figure 2
Figure 2. [11C]Temozolomide chromatography and radio TLC
A: Black and red lines correspond to UV (254 nm) and radioactivity, respectively. Product peak collected between 5.2 and 7.0 minutes. B: Aliquots of purified [11C]TMZ solution mixed with TMZ reference standard were analyzed by analytical HPLC (Column: Agilent Eclipse XDB-C18, 250 × 4.6 mm; mobile phase: 0.1% TFA in H2O:CH3CN, 97:3; flow rate: 2 mL/min). C: UV spectra of [11C]TMZ (red) and coinjection of [11C]TMZ solution mixed with TMZ reference standard (black). D: Radio TLC of purified [11C]TMZ (mobile phase: DCM: MeOH, 85:15).
Scheme 1
Scheme 1
Hydrolysis of TMZ to MTIC
Scheme 2
Scheme 2. Synthesis of [11C]TMZ via cycloaddition of 8 and 9
Reagents and conditions: (i) (a) Ni/H2, 350 °C; (b) I2, 740 °C; (ii) AgOCN/180 °C; (iii) DMSO, 100 °C, 10 min
Scheme 3
Scheme 3. Synthesis of nortemozolomide and [11C]temozolomide
Reagents and conditions: (i) NaNO2, aq. HCl (1.0 M), 0 °C, 5 min, 60%; (ii) (a) ClCO2Et, Et3N, THF, 0 °C, 45 min, (b) NaN3/ H2O, 0 °C, 1 h, 57% (2 steps); (iii) DMSO, N2 atm, overnight, rt, 44%; (iv) 3.0 N HCl, rt, 5 h, 44%; (v) CH3I, NaH / DMF, 0 °C, rt, 5 h; (vi) [11C]CH3I, NaH/ DMF, 0 °C, 3 min, 45 °C, 5 min

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