Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-11C]iomazenil

Ronald M. Baldwin; Andrew G. Horti; J. Douglas Bremner; Morgan D. Stratton; Robert F. Dannals; Hayden T. Ravert; Yolanda Zea-Ponce; Chin K. Ng; Holley M. Dey; Robert Soufer; Dennis S. Charney; Samuel M. Mazza; Richard B. Sparks; James B. Stubbs; Robert B. Innis

doi:10.1016/0969-8051(94)00139-B

Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-¹¹C]iomazenil

Ronald M. Baldwin, Andrew G. Horti, J. Douglas Bremner, Morgan D. Stratton, Robert F. Dannals, Hayden T. Ravert, Yolanda Zea-Ponce, Chin K. Ng, Holley M. Dey, Robert Soufer, Dennis S. Charney, Samuel M. Mazza, Richard B. Sparks, James B. Stubbs, Robert B. Innis

School of Medicine

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Abstract

The central benzodiazepine receptor tracer [N-methyl-¹¹C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [¹¹C]methyl iodide. The [¹¹C]CH₃I (prepared by reduction of [¹¹C]CO₂ with LiAlH₄ followed by reaction with HI) was reacted with noriomazenil in N,N-dimethylformamide and Bu₄N⁺OH^- for 1 min at 80 °C and purified by HPLC (C₁₈, 34% CH₃CN/H₂O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [¹¹C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [¹¹C]flumazenil PET and [¹²³I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [¹¹C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.

Original language	English (US)
Pages (from-to)	659-665
Number of pages	7
Journal	Nuclear Medicine and Biology
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/0969-8051(94)00139-B
State	Published - Jul 1995

ASJC Scopus subject areas

Molecular Medicine
Radiology Nuclear Medicine and imaging
Cancer Research

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Baldwin, R. M., Horti, A. G., Bremner, J. D., Stratton, M. D., Dannals, R. F., Ravert, H. T., Zea-Ponce, Y., Ng, C. K., Dey, H. M., Soufer, R., Charney, D. S., Mazza, S. M., Sparks, R. B., Stubbs, J. B., & Innis, R. B. (1995). Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-¹¹C]iomazenil. Nuclear Medicine and Biology, 22(5), 659-665. https://doi.org/10.1016/0969-8051(94)00139-B

Baldwin, RM, Horti, AG, Bremner, JD, Stratton, MD, Dannals, RF, Ravert, HT, Zea-Ponce, Y, Ng, CK, Dey, HM, Soufer, R, Charney, DS, Mazza, SM, Sparks, RB, Stubbs, JB & Innis, RB 1995, 'Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-¹¹C]iomazenil', Nuclear Medicine and Biology, vol. 22, no. 5, pp. 659-665. https://doi.org/10.1016/0969-8051(94)00139-B

@article{9fcd4e81f6d54b05a0370a4d533b8a14,

title = "Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-11C]iomazenil",

abstract = "The central benzodiazepine receptor tracer [N-methyl-11C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [11C]methyl iodide. The [11C]CH3I (prepared by reduction of [11C]CO2 with LiAlH4 followed by reaction with HI) was reacted with noriomazenil in N,N-dimethylformamide and Bu4N+OH- for 1 min at 80 °C and purified by HPLC (C18, 34% CH3CN/H2O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [11C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [11C]flumazenil PET and [123I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [11C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.",

author = "Baldwin, {Ronald M.} and Horti, {Andrew G.} and Bremner, {J. Douglas} and Stratton, {Morgan D.} and Dannals, {Robert F.} and Ravert, {Hayden T.} and Yolanda Zea-Ponce and Ng, {Chin K.} and Dey, {Holley M.} and Robert Soufer and Charney, {Dennis S.} and Mazza, {Samuel M.} and Sparks, {Richard B.} and Stubbs, {James B.} and Innis, {Robert B.}",

note = "Funding Information: Hoffmann La Rochc Co.. Ltd. for the generous gifts of iomazenil and noriomarenil, and Drs G. Westera and Buck of University Hospital Zurich for sharing their manuscript before publication. This work was funded in part by the Public Health Service (ROI MH 404140). Veterans Affairs National Center for the Study of Post-traumatic Stress Disorder. and VA Career Development Award to Dr Bremner. Radiation dosimetry calculations were performed under Interagency Agreement No. FDA 224-75-3016,D OE 40-286-7I . Oak Ridge Associated Universities performs complementary work for the US Department of Energy under contract DE-AC05-760R00033.",

year = "1995",

month = jul,

doi = "10.1016/0969-8051(94)00139-B",

language = "English (US)",

volume = "22",

pages = "659--665",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier Inc.",

number = "5",

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TY - JOUR

T1 - Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-11C]iomazenil

AU - Baldwin, Ronald M.

AU - Horti, Andrew G.

AU - Bremner, J. Douglas

AU - Stratton, Morgan D.

AU - Dannals, Robert F.

AU - Ravert, Hayden T.

AU - Zea-Ponce, Yolanda

AU - Ng, Chin K.

AU - Dey, Holley M.

AU - Soufer, Robert

AU - Charney, Dennis S.

AU - Mazza, Samuel M.

AU - Sparks, Richard B.

AU - Stubbs, James B.

AU - Innis, Robert B.

N1 - Funding Information: Hoffmann La Rochc Co.. Ltd. for the generous gifts of iomazenil and noriomarenil, and Drs G. Westera and Buck of University Hospital Zurich for sharing their manuscript before publication. This work was funded in part by the Public Health Service (ROI MH 404140). Veterans Affairs National Center for the Study of Post-traumatic Stress Disorder. and VA Career Development Award to Dr Bremner. Radiation dosimetry calculations were performed under Interagency Agreement No. FDA 224-75-3016,D OE 40-286-7I . Oak Ridge Associated Universities performs complementary work for the US Department of Energy under contract DE-AC05-760R00033.

PY - 1995/7

Y1 - 1995/7

N2 - The central benzodiazepine receptor tracer [N-methyl-11C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [11C]methyl iodide. The [11C]CH3I (prepared by reduction of [11C]CO2 with LiAlH4 followed by reaction with HI) was reacted with noriomazenil in N,N-dimethylformamide and Bu4N+OH- for 1 min at 80 °C and purified by HPLC (C18, 34% CH3CN/H2O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [11C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [11C]flumazenil PET and [123I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [11C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.

AB - The central benzodiazepine receptor tracer [N-methyl-11C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [11C]methyl iodide. The [11C]CH3I (prepared by reduction of [11C]CO2 with LiAlH4 followed by reaction with HI) was reacted with noriomazenil in N,N-dimethylformamide and Bu4N+OH- for 1 min at 80 °C and purified by HPLC (C18, 34% CH3CN/H2O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [11C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [11C]flumazenil PET and [123I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [11C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.

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Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-¹¹C]iomazenil

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