Evaluation of TSPO PET Ligands [F]VUIIS1009A and [F]VUIIS1009B: Tracers for Cancer Imaging

Overview

Journal Mol Imaging Biol

Publisher Springer

Specialties Molecular Biology
Radiology

Date 2016 Nov 18

PMID 27853987

Citations 10

Authors

Dewei Tang

Jun Li

Jason R Buck

Mohamed Noor Tantawy

Yan Xia

Joel M Harp

Michael L Nickels

Jens Meiler

H Charles Manning

Affiliations

Soon will be listed here.

Abstract

Purpose: Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.

Procedures: VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D H-N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [F]VUIIS1009A and [F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.

Results: Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [F]VUIIS1009A and [F]VUIIS1009B exhibited greater binding potential (k /k )in tumor tissue compared to [F]DPA-714. Interestingly, [F]VUIIS1009B exhibited significantly greater tumor uptake (V ) than [F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.

Conclusions: The novel PET ligand [F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

Citing Articles

Synthesis, In Silico and In Vitro Characterization of Novel ,-Substituted Pyrazolopyrimidine Acetamide Derivatives for the 18KDa Translocator Protein (TSPO).

Park J, Wasim S, Jung J, Kim M, Lee B, Alam M Pharmaceuticals (Basel). 2023; 16(4).

PMID: 37111333 PMC: 10142799. DOI: 10.3390/ph16040576.

Multi-Targeted Neutron Capture Therapy Combined with an 18 kDa Translocator Protein-Targeted Boron Compound Is an Effective Strategy in a Rat Brain Tumor Model.

Kashiwagi H, Hattori Y, Kawabata S, Kayama R, Yoshimura K, Fukuo Y Cancers (Basel). 2023; 15(4).

PMID: 36831378 PMC: 9953932. DOI: 10.3390/cancers15041034.

A rapid and systematic approach for the optimization of radio thin-layer chromatography resolution.

Laferriere-Holloway T, Rios A, Lu Y, Okoro C, van Dam R J Chromatogr A. 2022; 1687:463656.

PMID: 36463649 PMC: 9894532. DOI: 10.1016/j.chroma.2022.463656.

F-Radiolabeled Translocator Protein (TSPO) PET Tracers: Recent Development of TSPO Radioligands and Their Application to PET Study.

Luu T, Kim H Pharmaceutics. 2022; 14(11).

PMID: 36432736 PMC: 9697781. DOI: 10.3390/pharmaceutics14112545.

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.

References

Innis R, Cunningham V, Delforge J, Fujita M, Gjedde A, Gunn R . Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007; 27(9):1533-9. DOI: 10.1038/sj.jcbfm.9600493. View

Dhermain F, Hau P, Lanfermann H, Jacobs A, van den Bent M . Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol. 2010; 9(9):906-20. DOI: 10.1016/S1474-4422(10)70181-2. View

Maaser K, Grabowski P, Sutter A, Hopfner M, Foss H, Stein H . Overexpression of the peripheral benzodiazepine receptor is a relevant prognostic factor in stage III colorectal cancer. Clin Cancer Res. 2002; 8(10):3205-9. View

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

Murail S, Robert J, Coic Y, Neumann J, Ostuni M, Yao Z . Secondary and tertiary structures of the transmembrane domains of the translocator protein TSPO determined by NMR. Stabilization of the TSPO tertiary fold upon ligand binding. Biochim Biophys Acta. 2008; 1778(6):1375-81. DOI: 10.1016/j.bbamem.2008.03.012. View

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

Cheung Y, Nickels M, Tang D, Buck J, Manning H . Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[(18)F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. Bioorg Med Chem Lett. 2014; 24(18):4466-4471. PMC: 4163096. DOI: 10.1016/j.bmcl.2014.07.091. View

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

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

10.

Venturini I, Zeneroli M, Corsi L, Baraldi C, Ferrarese C, Pecora N . Diazepam binding inhibitor and total cholesterol plasma levels in cirrhosis and hepatocellular carcinoma. Regul Pept. 1998; 74(1):31-4. DOI: 10.1016/s0167-0115(98)00013-5. View

11.

Carmel I, Fares F, Leschiner S, Scherubl H, Weisinger G, Gavish M . Peripheral-type benzodiazepine receptors in the regulation of proliferation of MCF-7 human breast carcinoma cell line. Biochem Pharmacol. 1999; 58(2):273-8. DOI: 10.1016/s0006-2952(99)00093-3. View

12.

Wang J, Erickson J, Fuji R, Ramachandran S, Gao P, Dinavahi R . Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010; 18(3):207-19. PMC: 3078749. DOI: 10.1016/j.ccr.2010.08.009. View

13.

van Liempd S, Morrison D, Sysmans L, Nelis P, Mortishire-Smith R . Development and validation of a higher-throughput equilibrium dialysis assay for plasma protein binding. J Lab Autom. 2011; 16(1):56-67. DOI: 10.1016/j.jala.2010.06.002. View

14.

Maaser K, Hopfner M, Jansen A, Weisinger G, Gavish M, Kozikowski A . Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells. Br J Cancer. 2001; 85(11):1771-80. PMC: 2363981. DOI: 10.1054/bjoc.2001.2181. View

15.

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

16.

Batarseh A, Papadopoulos V . Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol. 2010; 327(1-2):1-12. PMC: 2922062. DOI: 10.1016/j.mce.2010.06.013. View

17.

Logan J . Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol. 2000; 27(7):661-70. DOI: 10.1016/s0969-8051(00)00137-2. View

18.

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

19.

Liu W, Le A, Hancock C, Lane A, Dang C, W-M Fan T . Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci U S A. 2012; 109(23):8983-8. PMC: 3384197. DOI: 10.1073/pnas.1203244109. View

20.

Manning H, Goebel T, Thompson R, Price R, Lee H, Bornhop D . Targeted molecular imaging agents for cellular-scale bimodal imaging. Bioconjug Chem. 2004; 15(6):1488-95. DOI: 10.1021/bc049904q. View