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. 2019 Nov-Dec:78-79:11-16.
doi: 10.1016/j.nucmedbio.2019.10.003. Epub 2019 Oct 22.

Development of a 18F-labeled PET radioligand for imaging 5-HT1B receptors: [18F]AZ10419096

Anton Lindberg  1 , Sangram Nag  2 , Magnus Schou  3 , Ryosuke Arakawa  2 , Tsuyoshi Nogami  2 , Mohammad Mahdi Moein  2 , Charles S Elmore  4 , Victor W Pike  5 , Christer Halldin  2
Affiliations

Development of a 18F-labeled PET radioligand for imaging 5-HT1B receptors: [18F]AZ10419096

Anton Lindberg et al. Nucl Med Biol. 2019 Nov-Dec.

Abstract

Introduction: In the last decade PET has been useful in studying and understanding the 5-HT1B receptor. [11C]AZ10419369 and [11C]P943 have been applied as radioligands in these studies. Both use carbon-11 (t1/2 = 20.4 min) as radionuclide, which limits the application to PET centres that have an on-site cyclotron and radiochemistry facilities. In this paper we report the synthesis and initial evaluation of the first fluorine-18 PET radioligand to image 5-HT1B receptors in brain, [18F]AZ10419096.

Materials and methods: A boronate-precursor for [18F]AZ10419096 was synthesized from an intermediate provided by AstraZeneca and was labeled with fluorine 18 using Cu-mediated radio-fluorination. [18F]AZ10419096 was used in PET baseline and pretreatment measurements in nonhuman primates. PET data were analyzed using SRTM using the cerebellum as reference region. Blood samples for radio-metabolite analysis were collected during PET measurements.

Results: Radio-fluorination gave [18F]AZ10419096 in sufficient amounts and molar activity and with high radiochemical purity to be applied in PET measurements. In a baseline PET measurement [18F]AZ10419096 showed a high brain uptake and regional distribution consistent with reported 5-HT1B receptor densities. In a pretreatment PET measurement, AR-A000002 (2.0 mg/kg) blocked the binding of [18F]AZ10419096 to 5-HT1B receptors in occipital cortex by 80%, thereby demonstrating high specific binding.

Conclusion: [18F]AZ10419096 is the first fluorine-18 PET radioligand for imaging 5-HT1B receptors in vivo with high specific binding and binding potential. [18F]AZ10419096 is a candidate for further development for use in clinical PET studies.

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Figures

Fig. 1.
Fig. 1.
Previously reported successful 5-HT1B PET radioligands (1–3) and [18F]AZ10419096 ([18F]4).
Fig. 2.
Fig. 2.
PET summation images (0–123 min); A, MRI images with ROIs delineated (red: occipital cortex, green: globus pallidus, orange: ventral striatum, blue: midbrain, yellow: thalamus, light blue: cerebellum); B, baseline experiment using [18F]AZ10419096; C, Pretreatment experiment with AR-A000002 (2.0 mg/kg) administrated 30 min before [18F]AZ10419096.
Fig. 3.
Fig. 3.
A. Regional time-activity curves of [18F]AZ10419096 at baseline PET measurement (SUV). B. Regional specific binding of [18F]AZ10419096 at baseline PET measurement.
Fig. 4.
Fig. 4.
A. Regional time-activity curves for occipital cortex and cerebellum at baseline and pretreatment PET measurements. B. Regional time-activity curves for globus pallidus at baseline and pretreatment PET measurements.
Fig. 5.
Fig. 5.
A. Radiochromatogram of sample taken from blood plasma at 60 min after injection of [18F]AZ10419096 in baseline PET measurement. B. Graph of unchanged radioligand in blood plasma samples during baseline PET measurements using [18F]AZ10419096 and [11C]AZ10419096 [5].
Fig. 6.
Fig. 6.
Comparison of BPND in different regions between [18F]AZ10419096 (grey) and [11C]AZ10419096 (black) [5]. BPND calculated by SRTM between 0 and 123 min using cerebellum as reference region.
Scheme 1.
Scheme 1.
Synthesis of precursor and radiolabeling of [18F]AZ10419096.
See this image and copyright information in PMC

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