Preclinical in vitro and in vivo evaluation of [11C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates

被引:0
|
作者
Piel, Isabel [1 ]
Constantinescu, Cristian C. [2 ]
Bethencourt, David de la Puente [1 ]
Bonsall, David R. [3 ]
Rabiner, Eugenii A. [3 ]
Zasadny, Kenneth R. [4 ]
Amenta, Amy Llopis [2 ]
Wells, Lisa A. [3 ]
Poethko, Thorsten [1 ]
Prange, Wolfgang [1 ]
Delbeck, Martina [1 ]
机构
[1] Bayer AG, Wuppertal, Germany
[2] Invicro LLC, New Haven, CT USA
[3] Invicro LLC, Hammersmith Hosp, London, England
[4] Invicro LLC, Needham, MA USA
来源
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM | 2024年
关键词
alpha-2C adrenergic receptor; non-human primate; ORM-13070; positron emission tomography; receptor occupancy; KINETIC-ANALYSIS; BRAIN; ALPHA(2C)-ADRENOCEPTORS; C-11-ORM-13070; TRACER; RADIOSYNTHESIS; NORADRENALINE;
D O I
10.1177/0271678X241291949
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This paper describes the preclinical validation of the radioligand [C-11]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (alpha R-2C) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central alpha R-2C. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [H-3]ORM-13070. BAY 292 bound to the same binding site as [H-3]ORM-13070 and generated a good specific binding signal, with greater selectivity for alpha R-2C. In non-human primates in vivo, [C-11]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the alpha R-2C. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC50 for BAY 292 is 33.39 +/- 11.91 ng/mL. This study aimed to demonstrate the suitability of [C-11]ORM-13070 as a PET-radioligand for the study of alpha R-2C in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292.
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页数:13
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