Preclinical Evaluation of a Novel TSPO PET Ligand 2-(7-Butyl-2-(4-(2-[F]Fluoroethoxy)phenyl)-5-Methylpyrazolo[1,5-a]Pyrimidin-3-yl)-N,N-Diethylacetamide (F-VUIIS1018A) to Image Glioma

Overview

Journal Mol Imaging Biol

Publisher Springer

Specialties Molecular Biology
Radiology

Date 2018 Jun 6

PMID 29869061

Citations 13

Authors

Dewei Tang

Jun Li

Michael L Nickels

Gang Huang

Allison S Cohen

H Charles Manning

Affiliations

Soon will be listed here.

Abstract

Purpose: There is an urgent need for the development of novel positron emission tomography (PET) tracers for glioma imaging. In this study, we developed a novel PET probe ([F]VUIIS1018A) by targeting translocator protein (TSPO), an imaging biomarker for glioma. The purpose of this preclinical study was to evaluate this novel TSPO probe for glioma imaging.

Procedures: In this study, we synthesized [F]VUIIS1018A and the precursor for radiosynthesis of [F]VUIIS1018A. TSPO binding affinity was confirmed using a radioligand competitive binding assay in C6 glioma cell lysate. Further, dynamic imaging studies were performed in rats using a microPET system. These studies include displacement and blocking studies for ligand reversibility and specificity evaluation, and compartment modeling of PET data for pharmacokinetic parameter measurement using metabolite-corrected arterial input functions and PMOD.

Results: Compared to previously reported TSPO tracers including [F]VUIIS1008 and [F]DPA-714, the novel tracer [F]VUIIS1018A demonstrated higher binding affinity and BP. Pretreatment with the cold analog [F]VUIIS1018A could partially block tumor accumulation of this novel tracer. Further, compartment modeling of this novel tracer also exhibited a greater tumor-to-background ratio, a higher tumor binding potential and a lower brain binding potential when compared with other TSPO probes, such as [F]DPA-714 and [F]VUIIS1008.

Conclusions: These studies illustrate that [F]VUIIS1018A can serve as a promising TSPO PET tracer for glioma imaging and potentially imaging of other solid tumors.

Citing Articles

Current advances in the structure-activity relationship (SAR) analysis of the old/new 18-kDa translocator protein ligands.

Singh P, Singh V, Gond C, Singh D, Tiwari A Mol Divers. 2024; .

PMID: 39630364 DOI: 10.1007/s11030-024-10963-0.

TSPO Radioligands for Neuroinflammation: An Overview.

Salerno S, Viviano M, Baglini E, Poggetti V, Giorgini D, Castagnoli J Molecules. 2024; 29(17).

PMID: 39275061 PMC: 11397380. DOI: 10.3390/molecules29174212.

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica.

van der Geest K, Sandovici M, Nienhuis P, Slart R, Heeringa P, Brouwer E Front Med (Lausanne). 2022; 9:902155.

PMID: 35733858 PMC: 9207253. DOI: 10.3389/fmed.2022.902155.

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.

Singh P, Adhikari A, Singh D, Gond C, Tiwari A ACS Omega. 2022; 7(17):14412-14429.

PMID: 35557664 PMC: 9089361. DOI: 10.1021/acsomega.2c00588.

Essential Principles and Recent Progress in the Development of TSPO PET Ligands for Neuroinflammation Imaging.

Viviano M, Barresi E, Simeon F, Costa B, Taliani S, Da Settimo F Curr Med Chem. 2022; 29(28):4862-4890.

PMID: 35352645 PMC: 10080361. DOI: 10.2174/0929867329666220329204054.

References

Rupprecht R, Papadopoulos V, Rammes G, Baghai T, Fan J, Akula N . Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010; 9(12):971-88. DOI: 10.1038/nrd3295. View

Buck J, McKinley E, Hight M, Fu A, Tang D, Smith R . Quantitative, preclinical PET of translocator protein expression in glioma using 18F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline. J Nucl Med. 2010; 52(1):107-14. PMC: 3027353. DOI: 10.2967/jnumed.110.081703. View

Zheng J, Boisgard R, Siquier-Pernet K, Decaudin D, Dolle F, Tavitian B . Differential expression of the 18 kDa translocator protein (TSPO) by neoplastic and inflammatory cells in mouse tumors of breast cancer. Mol Pharm. 2011; 8(3):823-32. DOI: 10.1021/mp100433c. View

Tang D, Nickels M, Tantawy M, Buck J, Manning H . Preclinical imaging evaluation of novel TSPO-PET ligand 2-(5,7-Diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([ (18)F]VUIIS1008) in glioma. Mol Imaging Biol. 2014; 16(6):813-20. PMC: 4372299. DOI: 10.1007/s11307-014-0743-2. View

Wyatt S, Manning H, Bai M, Bailey S, Gallant P, Ma G . Molecular imaging of the translocator protein (TSPO) in a pre-clinical model of breast cancer. Mol Imaging Biol. 2009; 12(3):349-58. PMC: 6544016. DOI: 10.1007/s11307-009-0270-8. View

Venneti S, Lopresti B, Wiley C . Molecular imaging of microglia/macrophages in the brain. Glia. 2012; 61(1):10-23. PMC: 3580157. DOI: 10.1002/glia.22357. View

Buck J, McKinley E, Fu A, Abel T, Thompson R, Chambless L . Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study. PLoS One. 2015; 10(10):e0141659. PMC: 4627825. DOI: 10.1371/journal.pone.0141659. View

Han Z, Slack R, Li W, Papadopoulos V . Expression of peripheral benzodiazepine receptor (PBR) in human tumors: relationship to breast, colorectal, and prostate tumor progression. J Recept Signal Transduct Res. 2003; 23(2-3):225-38. DOI: 10.1081/rrs-120025210. View

Winkeler A, Boisgard R, Awde A, Dubois A, Theze B, Zheng J . The translocator protein ligand [¹⁸F]DPA-714 images glioma and activated microglia in vivo. Eur J Nucl Med Mol Imaging. 2012; 39(5):811-23. PMC: 3326235. DOI: 10.1007/s00259-011-2041-4. View

10.

Vasdev N, Green D, Vines D, McLarty K, McCormick P, Moran M . Positron-emission tomography imaging of the TSPO with [(18)F]FEPPA in a preclinical breast cancer model. Cancer Biother Radiopharm. 2013; 28(3):254-9. DOI: 10.1089/cbr.2012.1196. View

11.

Tang D, Hight M, McKinley E, Fu A, Buck J, Smith R . Quantitative preclinical imaging of TSPO expression in glioma using N,N-diethyl-2-(2-(4-(2-18F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide. J Nucl Med. 2012; 53(2):287-94. PMC: 3391587. DOI: 10.2967/jnumed.111.095653. View

12.

Tang D, Li J, Buck J, Tantawy M, Xia Y, Harp J . Evaluation of TSPO PET Ligands [F]VUIIS1009A and [F]VUIIS1009B: Tracers for Cancer Imaging. Mol Imaging Biol. 2016; 19(4):578-588. PMC: 5634614. DOI: 10.1007/s11307-016-1027-9. View

13.

Black K, Ikezaki K, Toga A . Imaging of brain tumors using peripheral benzodiazepine receptor ligands. J Neurosurg. 1989; 71(1):113-8. DOI: 10.3171/jns.1989.71.1.0113. View

14.

Dimitrakopoulou-Strauss A, Seiz M, Tuettenberg J, Schmieder K, Eisenhut M, Haberkorn U . Pharmacokinetic studies of ⁶⁸Ga-labeled Bombesin (⁶⁸Ga-BZH₃) and F-18 FDG PET in patients with recurrent gliomas and comparison to grading: preliminary results. Clin Nucl Med. 2011; 36(2):101-8. DOI: 10.1097/RLU.0b013e318203bb24. View

15.

Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B . Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging. 2008; 35(12):2304-19. DOI: 10.1007/s00259-008-0908-9. View

16.

Tang D, McKinley E, Hight M, Uddin M, Harp J, Fu A . Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging. J Med Chem. 2013; 56(8):3429-33. PMC: 3648642. DOI: 10.1021/jm4001874. View

17.

Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V . Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Res. 1999; 59(4):831-42. View

18.

Venneti S, Lopresti B, Wiley C . The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol. 2006; 80(6):308-22. PMC: 1849976. DOI: 10.1016/j.pneurobio.2006.10.002. View

19.

Wu Y, Carson R . Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab. 2002; 22(12):1440-52. DOI: 10.1097/01.WCB.0000033967.83623.34. View

20.

Papadopoulos V, Baraldi M, Guilarte T, Knudsen T, Lacapere J, Lindemann P . Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006; 27(8):402-9. DOI: 10.1016/j.tips.2006.06.005. View