Syntheses and in vitro evaluation of fluorinated naphthoxazines as dopamine D2/D3 receptor agonists: radiosynthesis, ex vivo biodistribution and autoradiography of [¹⁸F]F-PHNO

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• 作者：Neil Vasdev ; Philip Seeman ; Arm ; o Garcia ; Winston T. Stableford ; José ; N. Nobrega ; Sylvain Houle ; Alan A. Wilson
• 关键词：PHNO ; Fluorine-18 ; PET ; Fluoroalkylation ; D2 ; Agonist
• 刊名：Nuclear Medicine and Biology
• 出版年：2007
• 期刊代码：43_09698051
• 类别：ph
• 出版时间：February 2007
• 卷：34
• 期：2
• 页码：195-203
• 文件大小：543 K

摘要

>Introduction

Carbon-11-labeled (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([¹¹C]-(+)-PHNO) is a dopamine D2/D3 agonist radioligand that is currently used to image the high-affinity state of dopamine receptors in humans with positron emission tomography (PET). The present study reports the preparation and evaluation of fluorinated (+)-PHNO derivatives.

Methods

Five fluorinated (+)-PHNO derivatives were synthesized and tested in vitro for inhibition of binding of [³H]domperidone in homogenates of rat striatum and inhibition of binding to [³H]-(+)-PHNO in homogenates of human-cloned D2Long receptors in Chinese hamster ovary cells and rat striatum. Radiolabeling with fluorine-18 was carried out for the most promising candidate, N-fluoropropyl-(+)-HNO (F-PHNO), and ex vivo biodistribution and autoradiography studies with this radiopharmaceutical were performed in rodents.

Results

(+)-PHNO and the fluorinated analogs inhibited binding of [³H]domperidone and [³H]-(+)-PHNO to the high- and low-affinity states of dopamine D2 receptors, consistent with D2 agonist behavior. The average dissociation constant at the high-affinity state of D2, K_i^High, was 0.4 nM for F-PHNO and proved to be equipotent with (+)-PHNO (0.7 nM). All other fluorinated derivatives were significantly less potent (K_i^High=2–102 nM). The most promising candidate, F-PHNO, was labeled with fluorine-18 in 5%uncorrected radiochemical yield, with respect to starting fluoride. Ex vivo biodistribution and autoradiography studies in rodents revealed that [¹⁸F]F-PHNO rapidly enters the rodent brain. However, this radiotracer does not reveal specific binding in the brain and is rapidly cleared.

Conclusions

Five novel dopamine D2/D3 agonists based on (+)-PHNO were synthesized and evaluated in vitro. F-PHNO was shown to behave as a potent D2 agonist in vitro and was therefore radiolabeled with fluorine-18. Despite the promising in vitro pharmacological profile, [¹⁸F]F-PHNO did not display in vivo behavior suitable to image dopaminergic receptor expression using PET.