Synthesis and Evaluation of Candidate PET Radioligands for Corticotropin-releasing Factor Type-1 Receptors

Overview

Journal Nucl Med Biol

Publisher Elsevier

Specialties Biology
Nuclear Medicine

Date 2014 May 6

PMID 24793011

Citations 8

Authors

Nicholas J Lodge

Yu-Wen Li

Frederick T Chin

Douglas D Dischino

Sami S Zoghbi

Jeffrey A Deskus

Ronald J Mattson

Masao Imaizumi

Rick Pieschl

Thaddeus F Molski

Masahiro Fujita

Heidi Dulac

Robert Zaczek

Joanne J Bronson

John E Macor

Robert B Innis

Victor W Pike

Affiliations

Soon will be listed here.

Abstract

Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold.

Methods: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [(125)I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [(3)H]BMS-728300.

Results: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [(3)H]BMS-728300 and the two (18)F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [(18)F]BMS-721313, [(18)F]BMS-732098 and [(11)C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro.

Conclusions: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.

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References

Lelas S, Wong H, Li Y, Heman K, Ward K, Zeller K . Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1.... J Pharmacol Exp Ther. 2004; 309(1):293-302. DOI: 10.1124/jpet.103.058784. View

Hsin L, Webster E, Chrousos G, Gold P, Eckelman W, Contoreggi C . Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d]pyrimidines: the development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor. Bioorg Med Chem Lett. 2000; 10(8):707-10. DOI: 10.1016/s0960-894x(00)00071-8. View

Muller M, Zimmermann S, Sillaber I, Hagemeyer T, Deussing J, Timpl P . Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci. 2003; 6(10):1100-7. DOI: 10.1038/nn1123. View

Zorrilla E, Heilig M, de Wit H, Shaham Y . Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend. 2013; 128(3):175-86. PMC: 3596012. DOI: 10.1016/j.drugalcdep.2012.12.017. View

Patel S, Gibson R . In vivo site-directed radiotracers: a mini-review. Nucl Med Biol. 2008; 35(8):805-15. DOI: 10.1016/j.nucmedbio.2008.10.002. View

Kehne J, Cain C . Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models. Pharmacol Ther. 2010; 128(3):460-87. PMC: 3373002. DOI: 10.1016/j.pharmthera.2010.08.011. View

Li Y, Hill G, Wong H, Kelly N, Ward K, Pierdomenico M . Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy. J Pharmacol Exp Ther. 2003; 305(1):86-96. DOI: 10.1124/jpet.102.045914. View

Zhang G, Huang N, Li Y, Qi X, Marshall A, Yan X . Pharmacological characterization of a novel nonpeptide antagonist radioligand, (+/-)-N-[2-methyl-4-methoxyphenyl]-1-(1-(methoxymethyl) propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine ([3H]SN003) for corticotropin-releasing factor1 receptors. J Pharmacol Exp Ther. 2003; 305(1):57-69. DOI: 10.1124/jpet.102.046128. View

Li Y, Fitzgerald L, Wong H, Lelas S, Zhang G, Lindner M . The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists. CNS Drug Rev. 2005; 11(1):21-52. PMC: 6741745. DOI: 10.1111/j.1527-3458.2005.tb00034.x. View

10.

Timpl P, Spanagel R, Sillaber I, Kresse A, Reul J, Stalla G . Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet. 1998; 19(2):162-6. DOI: 10.1038/520. View

11.

Sullivan G, Parsey R, Dileep Kumar J, Arango V, Kassir S, Huang Y . PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?. Nucl Med Biol. 2007; 34(4):353-61. PMC: 1933490. DOI: 10.1016/j.nucmedbio.2007.01.012. View

12.

Deskus J, Dischino D, Mattson R, Ditta J, Parker M, Denhart D . [18F](R)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(4-(2-fluoroethoxy)-2,5-dimethyl phenylamino)pyrazin-2(1H)-one: introduction of N3-phenylpyrazinones as potential CRF-R1 PET imaging agents. Bioorg Med Chem Lett. 2012; 22(21):6651-5. DOI: 10.1016/j.bmcl.2012.08.112. View

13.

Jagoda E, Contoreggi C, Lee M, Kao C, Szajek L, Listwak S . Autoradiographic visualization of corticotropin releasing hormone type 1 receptors with a nonpeptide ligand: synthesis of [(76)Br]MJL-1-109-2. J Med Chem. 2003; 46(17):3559-62. DOI: 10.1021/jm034077k. View

14.

Sanchez M, Young L, Plotsky P, Insel T . Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol. 1999; 408(3):365-77. View

15.

Ramsey S, Attkins N, Fish R, van der Graaf P . Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo. Br J Pharmacol. 2011; 164(3):992-1007. PMC: 3195921. DOI: 10.1111/j.1476-5381.2011.01390.x. View

16.

Nemeroff C, Owens M, Bissette G, Andorn A, Stanley M . Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry. 1988; 45(6):577-9. DOI: 10.1001/archpsyc.1988.01800300075009. View

17.

Overstreet D, Griebel G . Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression. Eur J Pharmacol. 2004; 497(1):49-53. DOI: 10.1016/j.ejphar.2004.06.035. View

18.

Coric V, Feldman H, Oren D, Shekhar A, Pultz J, Dockens R . Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety. 2010; 27(5):417-25. DOI: 10.1002/da.20695. View

19.

Britton D, Koob G, Rivier J, Vale W . Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty. Life Sci. 1982; 31(4):363-7. DOI: 10.1016/0024-3205(82)90416-7. View

20.

Martarello L, Kilts C, Ely T, Owens M, Nemeroff C, Camp M . Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor. Nucl Med Biol. 2001; 28(2):187-95. DOI: 10.1016/s0969-8051(00)00199-2. View