Key result
Novel PDE10A tracer AMG-7980 demonstrates high uptake and 10-fold striatal specificity in rat models.
Why the study?
A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and dose selection in clinical development.
The novel PDE10A tracer AMG-7980 demonstrates high specificity and saturable binding, providing a valuable tool for measuring in vivo target occupancy in CNS drug discovery.
Answers are grounded in this paper and cite their sources.
Supports PDE10A tracer development for CNS imaging; leaves open in vivo translation and clinical validation.
A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology.
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Hu et al. (2012) studied this question. AMG-7980 was evaluated on PDE10A affinity (K(D)) and target density (B(max)). The novel PDE10A tracer AMG-7980 demonstrated good striatal uptake, high specificity (striatum/thalamus ratio of 10), and a PDE10A affinity (K(D)) of 0.94 nM in rat models.
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