Single-step High-yield Radiosynthesis and Evaluation of a Sensitive 18F-labeled Ligand for Imaging Brain Peripheral Benzodiazepine Receptors with PET

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Jan 6

PMID 19119848

Citations 37

Authors

Emmanuelle Briard

Sami S Zoghbi

Fabrice G Simeon

Masao Imaizumi

Jonathan P Gourley

H Umesha Shetty

Shuiyu Lu

Masahiro Fujita

Robert B Innis

Victor W Pike

Affiliations

Soon will be listed here.

Abstract

Elevated levels of peripheral benzodiazepine receptors (PBR) are associated with activated microglia in their response to inflammation. Hence, PBR imaging in vivo is valuable for investigating brain inflammatory conditions. Sensitive, easily prepared, and readily available radioligands for imaging with positron emission tomography (PET) are desirable for this purpose. We describe a new 18F-labeled PBR radioligand, namely [18F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([18F]9). [18F]9 was produced easily through a single and highly efficient step, the reaction of [18F]fluoride ion with the corresponding bromo precursor, 8. Ligand 9 exhibited high affinity for PBR in vitro. PET showed that [18F]9 was avidly taken into monkey brain and gave a high ratio of PBR-specific to nonspecific binding. [18F]9 was devoid of defluorination in rat and monkey and gave predominantly polar radiometabolite(s). In rat, a low level radiometabolite of intermediate lipophilicity was identified as [18F]2-fluoro-N-(2-phenoxyphenyl)acetamide ([18F]11). [18F]9 is a promising radioligand for future imaging of PBR in living human brain.

Citing Articles

Translational Preclinical PET Imaging and Metabolic Evaluation of a New Cannabinoid 2 Receptor (CBR) Radioligand, ()--(3-(2-(2-[F]Fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide.

Auvity S, Attili B, Caille F, Goislard M, Cayla J, Hinnen F ACS Pharmacol Transl Sci. 2024; 7(10):3144-3154.

PMID: 39421654 PMC: 11480890. DOI: 10.1021/acsptsci.4c00348.

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.

PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator.

Belov V, Guehl N, Duvvuri S, Iredale P, Moon S, Dhaynaut M J Cereb Blood Flow Metab. 2024; 44(8):1329-1342.

PMID: 38477292 PMC: 11342722. DOI: 10.1177/0271678X241238820.

Quantitative Analysis of S1PR1 Expression in the Postmortem Multiple Sclerosis Central Nervous System.

Jiang H, Zhou C, Qiu L, Gropler R, Brier M, Wu G ACS Chem Neurosci. 2023; 14(22):4039-4050.

PMID: 37882753 PMC: 11037862. DOI: 10.1021/acschemneuro.3c00581.

Evaluation of -[C]PK11195 PET/MRI for Spinal Cord-Related Neuropathic Pain in Patients with Cervical Spinal Disorders.

Kitade M, Nakajima H, Tsujikawa T, Noriki S, Mori T, Kiyono Y J Clin Med. 2023; 12(1).

PMID: 36614916 PMC: 9821277. DOI: 10.3390/jcm12010116.

References

Pike V . Positron-emitting radioligands for studies in vivo-probes for human psychopharmacology. J Psychopharmacol. 2012; 7(2):139-58. DOI: 10.1177/026988119300700202. View

Gandelman M, Baldwin R, Zoghbi S, Zea-Ponce Y, Innis R . Evaluation of ultrafiltration for the free-fraction determination of single photon emission computed tomography (SPECT) radiotracers: beta-CIT, IBF, and iomazenil. J Pharm Sci. 1994; 83(7):1014-9. DOI: 10.1002/jps.2600830718. 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

Braestrup C, Albrechtsen R, Squires R . High densities of benzodiazepine receptors in human cortical areas. Nature. 1977; 269(5630):702-4. DOI: 10.1038/269702a0. View

Canat X, Carayon P, Bouaboula M, Cahard D, Shire D, Roque C . Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells. Life Sci. 1993; 52(1):107-18. DOI: 10.1016/0024-3205(93)90293-c. View

Maeda J, Suhara T, Zhang M, Okauchi T, Yasuno F, Ikoma Y . Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. Synapse. 2004; 52(4):283-91. DOI: 10.1002/syn.20027. View

Sykes T, Ruth T, Adam M . Synthesis and murine tissue uptake of sodium [18F]fluoroacetate. Int J Rad Appl Instrum B. 1986; 13(5):497-500. DOI: 10.1016/0883-2897(86)90126-1. View

Imaizumi M, Briard E, Zoghbi S, Gourley J, Hong J, Fujimura Y . Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors. Neuroimage. 2007; 39(3):1289-98. PMC: 2275117. DOI: 10.1016/j.neuroimage.2007.09.063. View

Zhang M, Kida T, Noguchi J, Furutsuka K, Maeda J, Suhara T . [(11)C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl Med Biol. 2003; 30(5):513-9. DOI: 10.1016/s0969-8051(03)00016-7. View

10.

Zhang M, Maeda J, Furutsuka K, Yoshida Y, Ogawa M, Suhara T . [18F]FMDAA1106 and [18F]FEDAA1106: two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR). Bioorg Med Chem Lett. 2002; 13(2):201-4. DOI: 10.1016/s0960-894x(02)00886-7. View

11.

Pascali C, Luthra S, Pike V, Price G, Ahier R, Hume S . The radiosynthesis of [18F]PK 14105 as an alternative radioligand for peripheral type benzodiazepine binding sites. Int J Rad Appl Instrum A. 1990; 41(5):477-82. DOI: 10.1016/0883-2889(90)90008-5. View

12.

Zavala F . Benzodiazepines, anxiety and immunity. Pharmacol Ther. 1998; 75(3):199-216. DOI: 10.1016/s0163-7258(97)00055-7. View

13.

Lang S . The role of peripheral benzodiazepine receptors (PBRs) in CNS pathophysiology. Curr Med Chem. 2002; 9(15):1411-5. DOI: 10.2174/0929867023369745. View

14.

Schoemaker H, Bliss M, Yamamura H . Specific high-affinity saturable binding of [3H] R05-4864 to benzodiazepine binding sites in the rat cerebral cortex. Eur J Pharmacol. 1981; 71(1):173-5. DOI: 10.1016/0014-2999(81)90405-2. View

15.

Okubo T, Yoshikawa R, Chaki S, Okuyama S, Nakazato A . Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands. Bioorg Med Chem. 2004; 12(2):423-38. DOI: 10.1016/j.bmc.2003.10.050. View

16.

Laruelle M, Slifstein M, Huang Y . Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. Mol Imaging Biol. 2003; 5(6):363-75. DOI: 10.1016/j.mibio.2003.09.009. View

17.

Papadopoulos V, Lecanu L, Brown R, Han Z, Yao Z . Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience. 2005; 138(3):749-56. DOI: 10.1016/j.neuroscience.2005.05.063. View

18.

Yu W, Wang E, Voll R, Miller A, Goodman M . Synthesis, fluorine-18 radiolabeling, and in vitro characterization of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinoline carboxamide derivatives as potential PET radioligands for imaging peripheral benzodiazepine receptor. Bioorg Med Chem. 2008; 16(11):6145-55. DOI: 10.1016/j.bmc.2008.04.046. View

19.

Wilson A, Garcia A, Parkes J, McCormick P, Stephenson K, Houle S . Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors. Nucl Med Biol. 2008; 35(3):305-14. DOI: 10.1016/j.nucmedbio.2007.12.009. View

20.

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