(R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function

Jun Toyohara, Mayumi Okamoto, Hiroki Aramaki, Yuto Zaitsu, Isao Shimizu, Kiichi Ishiwata

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Introduction: 2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[11C]EMP and characterise their properties as P-gp tracers. Methods: We synthesised (R)- and (S)-[11C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50mg/kg). We compared the brain pharmacokinetics of (R)-[11C]EMP and (R)-[11C]verapamil [(R)-[11C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET). Results: (R)- and (S)-[11C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [11C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[11C]EMP yields were ~30%, with specific activity>74GBq/μmol and radiochemical purity>99%. (R)-[11C]EMP showed significantly greater uptake in the mouse brain than (S)-[11C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[11C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[11C]EMP level was significantly lower than that of (R)-[11C]EMP 15minutes post-injection, whilst>88% of radioactivity in the brain was intact at 15minutes post-injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60minutes) of (R)-[11C]EMP was 2-fold higher than that of (R)-[11C]VER, but their AUCs after CsA pretreatment were comparable. Conclusions: (R)-[11C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[11C]VER.

Original languageEnglish
Pages (from-to)52-62
Number of pages11
JournalNuclear Medicine and Biology
Volume43
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

P-Glycoprotein
Brain
Radioactivity
Area Under Curve
Injections
Calcium Channel Blockers
Verapamil
Positron-Emission Tomography
Methylation
Cyclosporine
emopamil
Pharmacokinetics
Temperature

Keywords

  • Brain
  • Emopamil
  • Enantiomer
  • P-Glycoprotein
  • Positron emission tomography

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Toyohara, J., Okamoto, M., Aramaki, H., Zaitsu, Y., Shimizu, I., & Ishiwata, K. (2016). (R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function. Nuclear Medicine and Biology, 43(1), 52-62. https://doi.org/10.1016/j.nucmedbio.2015.09.001

(R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function. / Toyohara, Jun; Okamoto, Mayumi; Aramaki, Hiroki; Zaitsu, Yuto; Shimizu, Isao; Ishiwata, Kiichi.

In: Nuclear Medicine and Biology, Vol. 43, No. 1, 01.01.2016, p. 52-62.

Research output: Contribution to journalArticle

Toyohara, J, Okamoto, M, Aramaki, H, Zaitsu, Y, Shimizu, I & Ishiwata, K 2016, '(R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function', Nuclear Medicine and Biology, vol. 43, no. 1, pp. 52-62. https://doi.org/10.1016/j.nucmedbio.2015.09.001
Toyohara, Jun ; Okamoto, Mayumi ; Aramaki, Hiroki ; Zaitsu, Yuto ; Shimizu, Isao ; Ishiwata, Kiichi. / (R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function. In: Nuclear Medicine and Biology. 2016 ; Vol. 43, No. 1. pp. 52-62.
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abstract = "Introduction: 2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[11C]EMP and characterise their properties as P-gp tracers. Methods: We synthesised (R)- and (S)-[11C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50mg/kg). We compared the brain pharmacokinetics of (R)-[11C]EMP and (R)-[11C]verapamil [(R)-[11C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET). Results: (R)- and (S)-[11C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [11C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[11C]EMP yields were ~30{\%}, with specific activity>74GBq/μmol and radiochemical purity>99{\%}. (R)-[11C]EMP showed significantly greater uptake in the mouse brain than (S)-[11C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[11C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[11C]EMP level was significantly lower than that of (R)-[11C]EMP 15minutes post-injection, whilst>88{\%} of radioactivity in the brain was intact at 15minutes post-injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60minutes) of (R)-[11C]EMP was 2-fold higher than that of (R)-[11C]VER, but their AUCs after CsA pretreatment were comparable. Conclusions: (R)-[11C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[11C]VER.",
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AU - Okamoto, Mayumi

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AU - Shimizu, Isao

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N2 - Introduction: 2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[11C]EMP and characterise their properties as P-gp tracers. Methods: We synthesised (R)- and (S)-[11C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50mg/kg). We compared the brain pharmacokinetics of (R)-[11C]EMP and (R)-[11C]verapamil [(R)-[11C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET). Results: (R)- and (S)-[11C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [11C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[11C]EMP yields were ~30%, with specific activity>74GBq/μmol and radiochemical purity>99%. (R)-[11C]EMP showed significantly greater uptake in the mouse brain than (S)-[11C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[11C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[11C]EMP level was significantly lower than that of (R)-[11C]EMP 15minutes post-injection, whilst>88% of radioactivity in the brain was intact at 15minutes post-injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60minutes) of (R)-[11C]EMP was 2-fold higher than that of (R)-[11C]VER, but their AUCs after CsA pretreatment were comparable. Conclusions: (R)-[11C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[11C]VER.

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KW - Enantiomer

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