Dataset Information

Radiosynthesis and Biological Evaluation of [¹⁸F]R91150, a Selective 5-HT_2A Receptor Antagonist for PET-Imaging.

ABSTRACT: Serotonergic 5-HT_2A receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for in vivo quantification of receptor densities and receptor occupancy for therapy evaluation. Recently, the radiosynthesis of the selective 5-HT_2AR antagonist [¹⁸F]R91150 was reported. However, the six-step radiosynthesis is cumbersome and time-consuming with low radiochemical yields (RCYs) of <5%. In this work, [¹⁸F]R91150 was prepared using late-stage Cu-mediated radiofluorination to simplify its synthesis. The detailed protocol enabled us to obtain RCYs of 14 ± 1%, and the total synthesis time was reduced to 60 min. In addition, autoradiographic studies with [¹⁸F]R91150 in rat brain slices revealed the typical uptake pattern of 5-HT_2A receptor ligands.

SUBMITTER: Willmann M

PROVIDER: S-EPMC8155242 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Radiosynthesis and Biological Evaluation of [18F]R91150, a Selective 5-HT2A Receptor Antagonist for PET-Imaging.

Willmann Michael M Hegger Julian J Neumaier Bernd B Ermert Johannes J

ACS medicinal chemistry letters 20210401 5

Serotonergic 5-HT2A receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for in vivo quantification of receptor densities and receptor occupancy for therapy evaluation. ...[more]

PMID: 34055220

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Project description:IntroductionOur previous work demonstrated that the 99mTc renal tracer, 99mTc(CO)3(FEDA) (99mTc-1), has a rapid clearance comparable in rats to that of 131I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99mTc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18F renal imaging agent, Re(CO)3([18F]FEDA) (18F-1). Our goal was to develop an efficient one-step method for the preparation of 18F-1 and to compare its pharmacokinetic properties with those of 131I-OIH in rats.Methods18F-1 was prepared by the nucleophilic 18F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites.Results18F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of 131I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of 18F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [18F]fluoride.Conclusions18F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131I-OIH and high in vivo radiochemical stability. Not only is 18F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18F/99mTc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.

Dataset Information

Radiosynthesis and Biological Evaluation of [¹⁸F]R91150, a Selective 5-HT_2A Receptor Antagonist for PET-Imaging.

Publications

Radiosynthesis and Biological Evaluation of [<sup>18</sup>F]R91150, a Selective 5-HT<sub>2A</sub> Receptor Antagonist for PET-Imaging.

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