Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 2/2020

01-04-2020 | Parkinson's Disease | Research Article

An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ

Authors: Chao Zhao, Chunyi Liu, Jie Tang, Yingjiao Xu, Minhao Xie, Zhengping Chen

Published in: Molecular Imaging and Biology | Issue 2/2020

Login to get access

Abstract

Purpose

The aim of this study was to optimize the radiolabeling method of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) to fulfill the demand of preclinical and clinical application.

Procedures

Optimized labeling conditions were performed by altering the molar ratio of precursor to base (P/B), base species, solvents, reaction temperature, reaction time, and precursor concentration through manual radiosynthesis of [18F]FP-(+)-DTBZ. The conditions with the highest radiochemical yield (RCY) were applied to automated radiosynthesis, and the crude product was purified with a Sep-Pak Plus C18 cartridge. Quality control and stability of [18F]FP-(+)-DTBZ were carried out by HPLC. In vitro cellular uptake and blocking assays were conducted in human neuroblastoma cell line SH-SY5Y. In vivo imaging with small animal positron emission tomography (microPET) was performed with Sprague–Dawley rats.

Results

Under the optimized conditions (P/K2CO3 = 1:8, heating at 120 °C for 3 min in dimethyl sulfoxide), an RCY of 88.7 % was obtained with 1.0 mg precursor. The optimized reaction conditions were successfully applied to an automated module and gave a high activity yield (AY) of 30–55 % in about 40 min with a > 99.0 % radiochemical purity (RCP) and a > 44.4 GBq/μmol molar activity (Am). Stability test displayed that the RCP retained > 98.0 % in 8 h in saline and in phosphate buffer saline (PBS, pH 7.4). In vitro cellular uptake assay showed accumulation of [18F]FP-(+)-DTBZ in SH-SY5Y cells, which could be significantly inhibited by vesicular monoamine transporter 2 (VMAT2) inhibitor DTBZ. MicroPET images of rat brain displayed that the striatum showed the highest uptake with a standardized uptake value (SUV) of 3.91 ± 0.30 at ~ 70 min. Co-injection with DTBZ (1.0 mg/kg) resulted in a 75 % decrease of the striatal SUV, confirming the specificity of [18F]FP-(+)-DTBZ to VMAT2.

Conclusions

We obtained an optimized radiolabeling method of [18F]FP-(+)-DTBZ and successfully applied it to a commercial available module. The automated synthesis gave a high AY and RCP of [18F]FP-(+)-DTBZ with high and specific binding to VMAT2, facilitating its routine application for VMAT2 tracing.
Appendix
Available only for authorised users
Literature
1.
Pogarell O, Koch W, Gildehaus FJ, Kupsch A, Lindvall O, Oertel WH, Tatsch K (2006) Long-term assessment of striatal dopamine transporters in Parkinsonian patients with intrastriatal embryonic mesencephalic grafts. Eur J Nucl Med Mol Imaging 33:407–411CrossRef
2.
Miller GW, Erickson JD, Perez JT, Penland SN, Mash DC, Rye DB, Levey AI (1999) Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson’s disease. Exp Neurol 156:138–148CrossRef
3.
Goswami R, Ponde DE, Kung MP, Hou C, Kilbourn MR, Kung HF (2006) Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters. Nucl Med Biol 33:685–694CrossRef
4.
Kalliokoski T, Tuomela J, Haavisto L, Forsback S, Snellman A, Helin S, Grönroos TJ, Solin O, Haaparanta-Solin M (2014) 6-[18F]fluoro-L-DOPA uptake in the rat pancreas is dependent on the tracer metabolism. Mol Imaging Biol 16:403–411CrossRef
5.
Okamura N, Villemagne VL, Drago J, Pejoska S, Dhamija RK, Mulligan RS, Ellis JR, Ackermann U, O’Keefe G, Jones G, Kung HF, Pontecorvo MJ, Skovronsky D, Rowe CC (2010) In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with 18F-AV-133. J Nucl Med 51:223–228CrossRef
6.
Tsao HH, Lin KJ, Juang JH, Skovronsky DM, Yen TC, Wey SP, Kung MP (2010) Binding characteristics of 9-fluoropropyl-(+)-dihydrotetrabenzazine (AV-133) to the vesicular monoamine transporter type 2 in rats. Nucl Med Biol 37:413–419CrossRef
7.
Li X, Chen Z, Tang J, Liu C, Zou P, Huang H, Tan C, Yu H (2014) Synthesis and biological evaluation of 10-[11C]-dihydrotetrabenazine as a vesicular monoamine transporter 2 radioligand. Arch Pharm 347:313–319CrossRef
8.
Strome EM, Cepeda IL, Sossi V, Doudet DJ (2006) Evaluation of the integrity of the dopamine system in a rodent model of Parkinson’s disease: small animal positron emission tomography compared to behavioral assessment and autoradiography. Mol Imaging Biol 8:292–299CrossRef
9.
Alexander PK, Lie Y, Jones G, Sivaratnam C, Bozinvski S, Mulligan RS, Young K, Villemagne VL, Rowe CC (2017) Management impact of imaging brain vesicular monoamine transporter type 2 in clinically uncertain parkinsonian syndrome with [18F]-AV133 and PET. J Nucl Med 58:1815–1820CrossRef
10.
Waldmann CM, Gomez A, Marchis P, Bailey ST, Momcilovic M, Jones AE, Shackelford DB, Sadeghi S (2018) An automated multidose synthesis of the potentiometric PET probe 4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP). Mol Imaging Biol 20:205–212CrossRef
11.
Kung MP, Hou C, Goswami R, Ponde DE, Kilbourn MR, Kung HF (2007) Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters. Nucl Med Biol 34:239–246CrossRef
12.
Zhu L, Ploessl K, Kung HF (2014) PET/SPECT imaging agents for neurodegenerative diseases. Chem Soc Rev 43:6683–6691CrossRef
13.
Weng CC, Huang SL, Chen ZA, Lin KJ, Hsiao IT, Yen TC, Kung MP, Wey SP, Hsu CH (2017) [18F]FP-(+)-DTBZ PET study in a lactacystin-treated rat model of Parkinson disease. Ann Nucl Med 31:506–513CrossRef
14.
Chen Z, Tang J, Liu C, Li X, Huang H, Xu X, Yu H (2016) Effects of anesthetics on vesicular monoamine transporter type 2 binding to [18F]-FP-(+)-DTBZ: a biodistribution study in rat brain. Nucl Med Biol 43:124–129CrossRef
15.
Zhu L, Liu Y, Plossl K et al (2010) An improved radiosynthesis of [18F]AV-133: a PET imaging agent for vesicular monoamine transporter 2. Nucl Med Biol 37:133–141CrossRef
16.
Lin SC, Lin KJ, Hsiao IT, Hsieh CJ, Lin WY, Lu CS, Wey SP, Yen TC, Kung MP, Weng YH (2014) In vivo detection of monoaminergic degeneration in early Parkinson disease by 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine PET. J Nucl Med 55:73–79CrossRef
17.
Wood H (2014) Parkinson disease: [18F]DTBZ PET tracks dopaminergic degeneration in patients with Parkinson disease. Nat Rev Neurol 10:305CrossRef
18.
Hsiao IT, Weng YH, Hsieh CJ, Lin WY, Wey SP, Kung MP, Yen TC, Lu CS, Lin KJ (2014) Correlation of Parkinson disease severity and [18F]-DTBZ positron emission tomography. JAMA Neurol 71:758–766CrossRef
19.
Naganawa M, Lim K, Nabulsi NB, Lin SF, Labaree D, Ropchan J, Herold KC, Huang Y, Harris P, Ichise M, Cline GW, Carson RE (2018) Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of [18F]-FP-DTBZ in healthy subjects and patients with type 1 diabetes. Mol Imaging Biol 20:835–845CrossRef
20.
Lin KJ, Weng YH, Wey SP, Hsiao IT, Lu CS, Skovronsky D, Chang HP, Kung MP, Yen TC (2010) Whole-body biodistribution and radiation dosimetry of [18F]-FP-(+)-DTBZ ([18F]-AV-133): a novel vesicular monoamine transporter 2 imaging agent. J Nucl Med 51:1480–1485CrossRef
21.
Lee S-J, Oh S-J, Chi D-Y, Moon DH, Ryu JS (2012) High yielding [18F]fluorination method by fine control of the base. Bull Kor Chem Soc 33:2177–2180CrossRef
22.
Nebel N, Maschauer S, Hocke C, Hübner H, Gmeiner P, Prante O (2016) Optimization and synthesis of an18F-labeled dopamine D3receptor ligand using [18F]fluorophenylazocarboxylictert-butylester. J Label Compd Radiopharm 59:48–53CrossRef
23.
Lee SJ, Hyun JS, Oh SJ, Yu KH, Ryu JS (2013) Development of a new precursor-minimizing base control method and its application for the automated synthesis and SPE purification of [18F]fluoromisonidazole ([18F]FMISO). J Label Compd Radiopharm 56:731–735CrossRef
24.
Zheng P, Lieberman BP, Choi SR, Plöessl K, Kung HF (2011) Synthesis and biological evaluation of 3-alkyl-dihydrotetrabenazine derivatives as vesicular monoamine transporter-2 (VMAT2) ligands. Bioorg Med Chem Lett 21:3435–3438CrossRef
25.
acobson O, Kiesewetter DO, Chen X (2015) Fluorine-18 radiochemistry, labeling strategies and synthetic routes. Bioconjug Chem 26:1–18CrossRef
26.
Lee SJ, Oh SJ, Chi DY, Kang SH, Kil HS, Kim JS, Moon DH (2007) One-step high-radiochemical-yield synthesis of [18F]-FP-CIT using a protic solvent system. Nucl Med Biol 34:345–351CrossRef
27.
Seo J-W, Lee B-S, Lee S-J, Oh SJ, Chi DY (2011) Fast and easy drying method for the preparation of activated [18F]fluoride using polymer cartridge. Bull Kor Chem Soc 32:71–76CrossRef
Metadata
Title
An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ
Authors
Chao Zhao
Chunyi Liu
Jie Tang
Yingjiao Xu
Minhao Xie
Zhengping Chen
Publication date
01-04-2020
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 2/2020
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-019-01379-6

Other articles of this Issue 2/2020

Molecular Imaging and Biology 2/2020 Go to the issue

Research Article

Targeting VPAC1 Receptors for Imaging Glioblastoma

Research Article

Bifunctional Labeling of Rabbit Mesenchymal Stem Cells for MR Imaging and Fluorescence Microscopy

Letter to the Editor

Simultaneous PET/MRI in the Evaluation of Breast and Prostate Cancer Using Combined Na[18F]F and [18F]FDG: a Focus on Skeletal Lesions

Research Article

Validation of Parametric Methods for [11C]UCB-J PET Imaging Using Subcortical White Matter as Reference Tissue

Research Article

[124I]CLR1404 PET/CT in High-Grade Primary and Metastatic Brain Tumors

Research Article

Evaluating the Role of Amide Proton Transfer (APT)–Weighted Contrast, Optimized for Normalization and Region of Interest Selection, in Differentiation of Neoplastic and Infective Mass Lesions on 3T MRI