J Nucl Med. 2008; 49 (Supplement 1):209P
Neurosciences: Basic ScienceBasic Science Posters |
In vivo receptor occupancy using [N-methyl-3H3]AZ10419369, a serotonin 5HT1B receptor radiotracer
Donna Maier1,
Min Ding1,
Cindy Sobotka-Briner1,
Amy Medd1,
Mark Powell1,
Charles Elmore1,
M. Edward Pierson1 and
Ladislav Mrzljak1
1 CNS Discovery, AstraZeneca, Wilmington, Delaware
905
Objectives: Radiotracer tools suitable for PET studies often serve as preclinical tools for in vivo receptor occupancy. AZ10419369 has sub-nM affinity for the 5-HT1B receptor and compound properties preferable for an in vivo radiotracer.
Methods: In vitro saturation binding was conducted in guinea pig brain membranes for [N-methyl-3H3]AZ10419369 (0.14 - 10nM) with GR127935 (10 µM) for non-specific binding. For in vivo brain uptake and regional selectivity, guinea pigs were injected with [N-methyl-3H3]AZ10419369 (7.5 µCi/ml) and euthanized 15 to 90 min later. Radioactivity was measured by scintillation count in dissected brain regions (striatum/globus pallidus, cortex, midbrain and cerebellum). In vivo pharmacological selectivity for [N-methyl-3H3]AZ10419369 was determined by pretreatment with the 5HT1B antagonist, AR-A000002 (0.01 to 100 mg/kg, sc).
Results: [N-methyl-3H3]AZ10419369 synthesis (80 Ci/mmol) was efficient with high yield. [N-methyl-3H3]AZ10419369 showed high affinity in the guinea pig striatum/globus pallidus and substantia nigra (Kd = 1.9 and 1.5 nM). In vivo binding for [N-methyl-3H3]AZ10419369 was high in 5HT1B target regions (striatum/globus pallidus, cortex and substantia nigra) and low in the cerebellum, consistent with [N-methyl-3H3]AZ10419369 in vitro autoradiography in brain sections. AR-A000002 inhibited [N-methyl-3H3]-AZ10419369 binding in 5HT1B target regions.
Conclusions: Our findings using tritiated AZ10419369 in the guinea pig are consistent with [11C]AZ10419369 data in the primate brain using PET-imaging (Pierson et al., 2007). Our data indicate that [N-methyl-3H3]AZ10419369 is a 5HT1B receptor radiotracer and a useful pre-clinical tool for in vivo occupancy in the guinea pig brain.
Research Support: AstraZeneca Pharmaceuticals
