Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist

Benjamin H Rotstein; Steven H Liang; Vasily V Belov; Eli Livni; Dylan B Levine; Ali A Bonab; Mikhail I Papisov; Roy H Perlis; Neil Vasdev

doi:10.3390/molecules20069550

Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist

Molecules. 2015 May 26;20(6):9550-9. doi: 10.3390/molecules20069550.

Authors

Benjamin H Rotstein¹, Steven H Liang², Vasily V Belov^{3

4}, Eli Livni⁵, Dylan B Levine^{6

7}, Ali A Bonab^{8

9}, Mikhail I Papisov^{10

11}, Roy H Perlis¹², Neil Vasdev¹³

Affiliations

¹ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. rotstein.benjamin@mgh.harvard.edu.
² Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. liang.steven@mgh.harvard.edu.
³ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. vbelov@mgh.harvard.edu.
⁴ Department of Research, Shriners Hospitals for Children-Boston, 51 Blossom Street, Boston, MA 02114, USA. vbelov@mgh.harvard.edu.
⁵ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. elivni@mgh.harvard.edu.
⁶ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. dblevine@mgh.harvard.edu.
⁷ Department of Research, Shriners Hospitals for Children-Boston, 51 Blossom Street, Boston, MA 02114, USA. dblevine@mgh.harvard.edu.
⁸ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. bonab@pet.mgh.harvard.edu.
⁹ Department of Research, Shriners Hospitals for Children-Boston, 51 Blossom Street, Boston, MA 02114, USA. bonab@pet.mgh.harvard.edu.
¹⁰ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. papisov@helix.mgh.harvard.edu.
¹¹ Department of Research, Shriners Hospitals for Children-Boston, 51 Blossom Street, Boston, MA 02114, USA. papisov@helix.mgh.harvard.edu.
¹² Department of Psychiatry and Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. rperlis@mgh.harvard.edu.
¹³ Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. vasdev.neil@mgh.harvard.edu.

Abstract

In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.

Keywords: calcium channel blocker; carbon-11; isradipine; neuroimaging; positron emission tomography; radiosynthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Brain / ultrastructure
Calcium Channel Blockers / chemistry
Calcium Channel Blockers / metabolism
Calcium Channel Blockers / pharmacokinetics*
Calcium Channels / metabolism
Carbon Radioisotopes
Dimethylformamide / chemistry
Drug Evaluation, Preclinical
Half-Life
Hydrocarbons, Iodinated / chemistry*
Isotope Labeling / methods*
Isradipine / chemistry
Isradipine / metabolism
Isradipine / pharmacokinetics*
Male
Neuroimaging / methods*
Permeability
Positron-Emission Tomography
Quaternary Ammonium Compounds / chemistry
Radiopharmaceuticals / chemistry
Radiopharmaceuticals / metabolism
Radiopharmaceuticals / pharmacokinetics*
Rats
Rats, Sprague-Dawley

Substances

Calcium Channel Blockers
Calcium Channels
Carbon Radioisotopes
Hydrocarbons, Iodinated
Quaternary Ammonium Compounds
Radiopharmaceuticals
Dimethylformamide
tetrabutylammonium
methyl iodide
Isradipine

Grants and funding

K01 DA038000/DA/NIDA NIH HHS/United States