Discovery of a highly specific 18F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination

Acta Pharmaceutica Sinica B

Lingling Zhang¹  Jian Rong¹  Huangcan Chen¹  Yi Xu¹  Steven H. Liang¹  Huiyi Wei²  Chao Che²  Guocong Li³  Jiyun Sun³  Lu Hou³  Qijun Cai³  Ahmed Haider³  Lu Wang³  Zhiwei Xiao³  Chunyu Zhao³  Junjie Wei⁴  Weibin Zhang⁵  Yuefeng Li⁵  Shiyu Yuan⁵  Sen Yan⁶  Shaojuan Zhang⁷  Hai-Bin Luo⁷ 

[1] Department of Radiology, Harvard Medical School, Boston, MA 02114, USA;;Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital &Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China;Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China;;Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital &Guangdong Landau Biotechnology Co. Ltd., Guangzhou 510555, China;State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China;

关键词: Phosphodiesterase 10A;    PET radioligand;    18F;    Spirocyclic iodonium ylide;    Nonhuman primate;    Target occupancy;   

DOI  :  

来源: DOAJ

【 摘 要 】

As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel 18F-aryl PDE10A PET radioligand, codenamed [18F]P10A-1910 ([18F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [18F]9 possessed good in vitro binding affinity (IC50 = 2.1 nmol/L) and selectivity towards PDE10A. Further, [18F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (Papp > 10 × 10−6 cm/s in MDCK-MDR1 cells). PET imaging studies of [18F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [18F]9 when compared to the current reference standard for PDE10A-targeted PET, [18F]MNI659. Further, dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [18F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [18F]9 is a promising PDE10A PET radioligand for clinical translation.

【 授权许可】

Unknown