Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

Synthesis and Preclinical Evaluation of [11C]AZ11895530 for PET Imaging of the Serotonin 1A Receptor.

The serotonin 1A (5-HT1A) receptor is a G-protein-coupled receptor implicated in the pathophysiology of several neuropsychiatric and neurodegenerative disorders. We here report the preparation of two candidate 5-HT1A radioligands, [11C]AZ11132132 ([11C]3) and [11C]AZ11895530 ([11C]4), and their subsequent evaluation in vitro using autoradiography and in vivo using positron emission tomography (PET). Compounds 3 and 4 were radiolabeled at high radiochemical purity (>99%) and high molar activity (>38 GBq/µmol) by heteroatom methylation with [11C]methyl iodide. Autoradiography on whole hemispheres from post-mortem human brain revealed substantial nonspecific binding of [11C]3, while the binding of [11C]4 to brain tissue was consistent with the distribution of 5-HT1A receptors and sensitive to co-incubation with the reference 5-HT1A antagonist WAY-100635 (10 µM). Following intravenous injection of [11C]4 into a cynomolgus monkey, brain radioactivity concentration (Cmax ∼ 2.2 SUV) was high whereafter it decreased rapidly. The regional binding potential (BPND) values were calculated using the simplified reference tissue model with cerebellum as reference region. The values varied between 0.2 and 1.0 for temporal cortex, raphe nuclei, frontal cortex, and hippocampus which is consistent with the known 5-HT1A expression pattern. After pretreatment with WAY100635 (0.5 mg/kg), a homogeneous distribution of radioactivity was observed in non-human primate (NHP) brain. Although [11C]4 fulfilled important criteria for successful in vivo neuroimaging, including good blood-brain-barrier permeability and high specific binding in vitro to human brain tissue, the regional BPND values for [11C]4 in NHP brain were low when compared to those obtained with existing radioligands and thus do not merit further investigation of [11C]4. Evaluation of structurally related analogues is underway in our laboratory to identify improved candidates for clinical imaging.