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Concise and Scalable Radiosynthesis of (+)-[¹⁸F]MDL100907 as a Serotonin 5-HT_2A Receptor Antagonist for PET.

ABSTRACT: 5-Hydroxytryptamine (5-HT_2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [¹⁸F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [¹⁸F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [¹⁸F]MDL100907. The radiofluorination was performed on a ¹⁸F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind-Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [¹⁸F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [¹⁸F]MDL100907 in high molar activity (2.1 Ci/μmol) and compared it to [¹¹C]MDL100907 in the brain of a nonhuman primate.

SUBMITTER: Chavan LN

PROVIDER: S-EPMC10557077 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET.

Chavan Lahu N LN Voll Ronald R Sanchez Mar M MM Nye Jonathon A JA Goodman Mark M MM

ACS chemical neuroscience 20230925 19

5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and ...[more]

PMID: 37748194

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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

Concise and Scalable Radiosynthesis of (+)-[¹⁸F]MDL100907 as a Serotonin 5-HT_2A Receptor Antagonist for PET.

Publications

Concise and Scalable Radiosynthesis of (+)-[<sup>18</sup>F]MDL100907 as a Serotonin 5-HT<sub>2A</sub> Receptor Antagonist for PET.

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