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20.07.2020 | Research Article

Synthesis and Characterization of 9-(4-[¹⁸F]Fluoro-3-(hydroxymethyl)butyl)-2-(phenylthio)-6-oxopurine as a Novel PET Agent for Mutant Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Imaging

verfasst von: Takeshi Fuchigami, Tom Haywood, Gayatri Gowrishankar, David Anders, Mohammad Namavari, Mirwais Wardak, Sanjiv Sam Gambhir

Erschienen in: Molecular Imaging and Biology | Ausgabe 5/2020

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Abstract

Purpose

[¹⁸F]FHBG has been used as a positron emission tomography (PET) imaging tracer for the monitoring of herpes simplex virus type 1 thymidine kinase (HSV1-tk), a reporter gene for cell and gene therapy in humans. However, this tracer shows inadequate blood-brain barrier (BBB) penetration and, therefore, would be limited for accurate quantification of reporter gene expression in the brain. Here, we report the synthesis and evaluation of 9-(4-[¹⁸F]fluoro-3-(hydroxymethyl)butyl)-2(phenylthio)-6-oxopurine ([¹⁸F]FHBT) as a new PET tracer for imaging reporter gene expression of HSV1-tk and its mutant HSV1-sr39tk, with the aim of improved BBB penetration.

Procedures

[¹⁸F]FHBT was prepared by using a tosylate precursor and [¹⁸F]KF. The cellular uptake of [¹⁸F]FHBT was performed in HSV1-sr39tk-positive (+) or HSV1-sr39tk-negative (−) MDA-MB-231 breast cancer cells. The specificity of [¹⁸F]FHBT to assess HSV1-sr39tk expression was evaluated by in vitro blocking studies using 1 mM of ganciclovir (GCV). Penetration of [¹⁸F]FHBT and [¹⁸F]FHBG across the BBB was assessed by dynamic PET imaging studies in normal mice.

Results

The tosylate precursor reacted with [¹⁸F]KF using Kryptofix2.2.2 followed by deprotection to give [¹⁸F]FHBT in 10 % radiochemical yield (decay-corrected). The uptake of [¹⁸F]FHBT in HSV1-sr39tk (+) cells was significantly higher than that of HSV1-sr39tk (−) cells. In the presence of GCV (1 mM), the uptake of [¹⁸F]FHBT was significantly decreased, indicating that [¹⁸F]FHBT serves as a selective substrate of HSV1-sr39TK. PET images and time-activity curves of [¹⁸F]FHBT in the brain regions showed similar initial brain uptakes (~ 12.75 min) as [¹⁸F]FHBG (P > 0.855). Slower washout of [¹⁸F]FHBT was observed at the later time points (17.75 − 57.75 min, P > 0.207).

Conclusions

Although [¹⁸F]FHBT showed no statistically significant improvement of BBB permeability compared with [¹⁸F]FHBG, we have demonstrated that the 2-(phenylthio)-6-oxopurine backbone can serve as a novel scaffold for developing HSV1-tk/HSV1-sr39tk reporter gene imaging agents for additional research in the future.

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Li M, Wang Y, Liu M, Lan X (2018) Multimodality reporter gene imaging: construction strategies and application. Theranostics 8:2954–2973CrossRef

Haywood T, Beinat C, Gowrishankar G, Patel CB, Alam IS, Murty S, Gambhir SS (2019) Positron emission tomography reporter gene strategy for use in the central nervous system. Proc Natl Acad Sci U S A 116:11402–11407CrossRef

Min JJ, Gambhir SS (2008) Molecular imaging of PET reporter gene expression. Handb Exp Pharmacol:277–303

Brader P, Serganova I, Blasberg RG (2013) Noninvasive molecular imaging using reporter genes. J Nucl Med 54:167–172CrossRef

Yaghoubi SS, Campbell DO, Radu CG, Czernin J (2012) Positron emission tomography reporter genes and reporter probes: gene and cell therapy applications. Theranostics 2:374–391CrossRef

Yaghoubi SS, Barrio JR, Namavari M, Satyamurthy N, Phelps ME, Herschman HR, Gambhir SS (2005) Imaging progress of herpes simplex virus type 1 thymidine kinase suicide gene therapy in living subjects with positron emission tomography. Cancer Gene Ther 12:329–339CrossRef

Alauddin MM, Shahinian A, Park R, Tohme M, Fissekis JD, Conti PS (2007) In vivo evaluation of 2′-deoxy-2′-[¹⁸F]fluoro-5-iodo-1-beta-D-arabinofuranosyluracil ([¹⁸F]FIAU) and 2′-deoxy-2′-[¹⁸F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil ([¹⁸F]FEAU) as markers for suicide gene expression. Eur J Nucl Med Mol Imaging 34:822–829CrossRef

Miyagawa T, Gogiberidze G, Serganova I, Cai S, Balatoni JA, Thaler HT, Ageyeva L, Pillarsetty N, Finn RD, Blasberg RG (2008) Imaging of HSV-tk reporter gene expression: comparison between [18F]FEAU, [18F]FFEAU, and other imaging probes. J Nucl Med 49:637–648CrossRef

Brust P, Haubner R, Friedrich A, Scheunemann M, Anton M, Koufaki ON, Hauses M, Noll S, Noll B, Haberkorn U, Schackert G, Schackert HK, Avril N, Johannsen B (2001) Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression. Eur J Nucl Med 28:721–729CrossRef

10.

Alauddin MM, Conti PS (1998) Synthesis and preliminary evaluation of 9-(4-[¹⁸F]-fluoro-3-hydroxymethylbutyl)guanine ([¹⁸F]FHBG): a new potential imaging agent for viral infection and gene therapy using PET. Nucl Med Biol 25:175–180CrossRef

11.

Penuelas I, Haberkorn U, Yaghoubi S, Gambhir SS (2005) Gene therapy imaging in patients for oncological applications. Eur J Nucl Med Mol Imaging 32(Suppl 2):S384–S403CrossRef

12.

Yaghoubi SS, Jensen MC, Satyamurthy N, Budhiraja S, Paik D, Czernin J, Gambhir SS (2009) Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat Clin Pract Oncol 6:53–58CrossRef

13.

Keu KV, Witney TH, Yaghoubi S et al (2017) Reporter gene imaging of targeted T cell immunotherapy in recurrent glioma. Sci Transl Med 9:eaag2196CrossRef

14.

Black ME, Newcomb TG, Wilson HM, Loeb LA (1996) Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc Natl Acad Sci U S A 93:3525–3529CrossRef

15.

Yaghoubi SS, Gambhir SS (2007) PET imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) or mutant HSV1-sr39tk reporter gene expression in mice and humans using [18F]FHBG. Nat Protoc 1:3069–3075CrossRef

16.

Martinez-Quintanilla J, Bhere D, Heidari P, He D, Mahmood U, Shah K (2013) Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors. Stem Cells 31:1706–1714CrossRef

17.

Salabert AS, Vaysse L, Beaurain M et al (2017) Imaging grafted cells with [18F]FHBG using an optimized HSV1-TK mammalian expression vector in a brain injury rodent model. PloS One 12

18.

Cunningham VJ, Parker CA, Rabiner EA, Gee AD, Gunn RN (2005) PET studies in drug development: methodological considerations. Drug Discov Today Technol 2:311–315CrossRef

19.

Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2:541–553CrossRef

20.

Manikowski A, Verri A, Lossani A, Gebhardt BM, Gambino J, Focher F, Spadari S, Wright GE (2005) Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo. J Med Chem 48:3919–3929CrossRef

21.

Sekar TV, Paulmurugan R (2013) ³H-Penciclovir (³H-PCV) uptake assay. Bio-protocol 3

22.

Sekar TV, Foygel K, Ilovich O, Paulmurugan R (2014) Noninvasive theranostic imaging of HSV1-sr39TK-NTR/GCV-CB1954 dual-prodrug therapy in metastatic lung lesions of MDA-MB-231 triple negative breast cancer in mice. Theranostics 4:460–474CrossRef

23.

Zhang L, Villalobos A, Beck EM, Bocan T, Chappie TA, Chen L, Grimwood S, Heck SD, Helal CJ, Hou X, Humphrey JM, Lu J, Skaddan MB, McCarthy TJ, Verhoest PR, Wager TT, Zasadny K (2013) Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligand. J Med Chem 56:4568–4579CrossRef

24.

ADMET Predictor™ [computer program], Simulations Plus, Inc., Lancaster, California, USA

25.

Field AK, Davies ME, DeWitt C, Perry HC, Liou R, Germershausen J, Karkas JD, Ashton WT, Johnston DB, Tolman RL (1983) 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci U S A 80:4139–4143CrossRef

26.

Zheng QH, Wang JQ, Liu X, Fei X, Mock BH, Glick-Wilson BE, Sullivan ML, Raikwar SP, Gardner TA, Kao C, Hutchins GD (2004) An improved Total synthesis of PET HSV-tk gene reporter probe 9-(4-[¹⁸F]Fluoro-3-hydroxymethylbutyl)guanine ([¹⁸F]FHBG). Synth Commun 34:689–704CrossRef

27.

RNA-seq of 934 human cancer cell lines from the Cancer Cell Line Encyclopedia. EMBL-EBI Expression Atlas

28.

Alauddin MM, Shahinian A, Gordon EM, Conti PS (2004) Direct comparison of radiolabeled probes FMAU, FHBG, and FHPG as PET imaging agents for HSV1-tk expression in a human breast cancer model. Mol Imaging 3:76–84CrossRef

29.

Min JJ, Iyer M, Gambhir SS (2003) Comparison of [¹⁸F]FHBG and [¹⁴C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection. Eur J Nucl Med Mol Imaging 30:1547–1560CrossRef

30.

Kung HF, Choi SR, Qu W, Zhang W, Skovronsky D (2010) 18F stilbenes and styrylpyridines for PET imaging of Aβ plaques in Alzheimer’s disease: a miniperspective. J Med Chem 53:933–941CrossRef

31.

Yaghoubi S, Barrio JR, Dahlbom M, Iyer M, Namavari M, Satyamurthy N, Goldman R, Herschman HR, Phelps ME, Gambhir SS (2001) Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. J Nucl Med 42:1225–1234PubMed

32.

Wager TT, Hou X, Verhoest PR, Villalobos A (2010) Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem Neurosci 1:435–449CrossRef

Titel: Synthesis and Characterization of 9-(4-[18F]Fluoro-3-(hydroxymethyl)butyl)-2-(phenylthio)-6-oxopurine as a Novel PET Agent for Mutant Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Imaging
verfasst von: Takeshi Fuchigami
Tom Haywood
Gayatri Gowrishankar
David Anders
Mohammad Namavari
Mirwais Wardak
Sanjiv Sam Gambhir
Publikationsdatum: 20.07.2020
Verlag: Springer International Publishing
Erschienen in: Molecular Imaging and Biology / Ausgabe 5/2020
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-020-01517-5

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Synthesis and Characterization of 9-(4-[¹⁸F]Fluoro-3-(hydroxymethyl)butyl)-2-(phenylthio)-6-oxopurine as a Novel PET Agent for Mutant Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Imaging

Abstract

Purpose

Procedures

Results

Conclusions

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