Abstract
PurposeThe α2-adrenoceptors mediate many effects of norepinephrine and epinephrine, and participate in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. Of the three receptor subtypes, only α2A and α2C are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α2-adrenoceptors has been limited to the α2C subtype. Here, we report the synthesis of 6-[18F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α2A-adrenoceptors, and its preclinical evaluation in rats and mice.Procedures6-[18F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [18F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α2A-knockout (KO) and wild-type (WT) mice for subtype selectivity. In vivo PET imaging and ex vivo brain autoradiography were performed to determine the tracer distribution in the brain. The specificity of the tracer for the target was determined by pretreatment with the subtype-non-selective α2-agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[18F]fluoro-marsanidine were also analyzed.Results6-[18F]Fluoro-marsanidine was synthesized with [18F]Selectfluor bis(triflate) in a radiochemical yield of 6.4 ± 1.7 %. The molar activity was 3.1 to 26.6 GBq/μmol, and the radiochemical purity was > 99 %. In vivo studies in mice revealed lower uptake in the brains of α2A-KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α2A-adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[18F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice.Conclusion6-[18F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α2A-adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[18F]fluoro-marsanidine unsuitable for α2A-adrenoceptor targeting in rodents in vivo.
Highlights
The adrenergic system participates in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions
A fluorine atom can conveniently be incorporated into the 6-position of the marsanidine structure with Selectfluor bis(triflate) [26] to obtain 6-fluoro-marsanidine, in which its F-18-labeled form constitutes a tracer candidate for α2A-adrenoceptor imaging with positron emission tomography (PET)
The uptake of the tracer was determined in the brain and peripheral organs of both rats and mice in vivo using PET/computed tomography (CT) and ex vivo using autoradiography and organ radioactivity counting
Summary
The adrenergic system participates in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. In 2014, Arponen et al reported an α2C-selective PET tracer, [11C]ORM-13070 This tracer was evaluated in mice devoid of α2A-adrenoceptors and mice lacking both α2A- and α2Cadrenoceptors in order to confirm its high subtype selectivity [23] and has since been introduced for human use [24]. 6-Fluoro-marsanidine was demonstrated to have high α2A-adrenoceptor selectivity over the other two receptor subtypes. A fluorine atom can conveniently be incorporated into the 6-position of the marsanidine structure with Selectfluor bis(triflate) [26] to obtain 6-fluoro-marsanidine, in which its F-18-labeled form constitutes a tracer candidate for α2A-adrenoceptor imaging with PET. The uptake of the tracer was determined in the brain and peripheral organs of both rats and mice in vivo using PET/computed tomography (CT) and ex vivo using autoradiography and organ radioactivity counting. The amount of nonmetabolized 6-[18F]fluoro-marsanidine in plasma and brain homogenates was determined by thin-layer chromatography combined with autoradiography (radioTLC)
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