Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate.
BACKGROUND
N-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure.


METHODS
AZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [(11)C]pivalate was obtained via (11)C-carboxylation of tert-butyl lithium. The target compound, [(11)C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [(11)C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino-4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey.


RESULTS
The overall radiochemical yield of final formulated radiochemically pure (>99%) [(11)C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13GBq/μmol at time of administration (58min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous.


CONCLUSIONS
AZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure.
AstraZeneca Translational Sciences Centre, PET CoE, Dept of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, SE-17176 Stockholm, Sweden. magnus.schou@astrazeneca.com
Magnus
M
Schou
Katarina
K
Varnäs
Aurelija
A
Jucaite
Balázs
B
Gulyás
Christer
C
Halldin
Lars
L
Farde
D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D001921:Brain / Q000000981:diagnostic imaging; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry; D002250:Carbon Radioisotopes; D007553:Isotope Labeling; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography / Q000379:methods*; D011829:Radiation Dosage; D011854:Radiochemistry; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry
D001562:Benzimidazoles; D063386:Cannabinoid Receptor Agonists; D002250:Carbon Radioisotopes; C582877:N-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H-benzo(d)imidazol-5-yl)ethanesulfonamide; D043882:Receptors, Cannabinoid; D013449:Sulfonamides