Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity

S. Nag, G. Kettschau, T. Heinrich, A. Varrone, L. Lehmann, B. Gulyas, A. Thiele, E. Keller, C. Halldin

Research output: Contribution to journalArticle

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Abstract

The aim of this project was to synthesize and evaluate three novel fluorine-18 labeled derivatives of propargyl amine as potential PET radioligands to visualize monoamine oxidase B (MAO-B) activity. The three fluorinated derivatives of propargyl amine ((S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)-pent- 4-en-2-amine (5), (S)-N-(1-fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn- 1-amine (10) and (S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine (15)) were synthesized in multi-step organic syntheses. IC50 values for inhibition were determined for compounds 5, 10 and 15 in order to determine their specificity for binding to MAO-B. Compound 5 inhibited MAO-B with an IC50 of 664 ± 48.08 nM. No further investigation was carried out with this compound. Compound 10 inhibited MAO-B with an IC50 of 208.5 ± 13.44 nM and compound 15 featured an IC50 of 131.5 ± 0.71 nM for its MAO-B inhibitory activity. None of the compounds inhibited MAO-A activity (IC50 > 2 μM). The fluorine-18 labeled analogues of the two higher binding affinity compounds (10 and 15) (S)-N-(1-[18F]fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn-1- amine (16) and (S)-1-[18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan- 2-amine (18) were both prepared from the corresponding precursors 9A, 9B and 14A, 14B by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography experiments on human postmortem brain tissue sections were performed with 16 and 18. Only compound 18 demonstrated a high selectivity for MAO-B over MAO-A and was, therefore, chosen for further examination by PET in a cynomolgus monkey. The initial uptake of 18 in the monkey brain was 250% SUV at 4 min post injection. The highest uptake of radioactivity was observed in the striatum and thalamus, regions with high MAO-B activity, whereas lower levels of radioactivity were detected in the cortex and cerebellum. The percentage of unchanged radioligand 18 was 30% in plasma at 90 min post injection. In conclusion, compound 18 is a selective inhibitor of MAO-B in vitro and demonstrated a MAO-B specific binding pattern in vivo by PET in monkey. It can, therefore, be considered as a candidate for further investigation in human by PET.

Original languageEnglish
Pages (from-to)186-195
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

Fingerprint

Fluorine
Monoamine Oxidase
Amines
Inhibitory Concentration 50
Radioactivity
Haplorhini
Brain
Derivatives
Synthetic Chemistry Techniques
Injections
Macaca fascicularis
Autoradiography
Thalamus
Cerebellum
Substitution reactions
Tissue
Plasmas

Keywords

  • Autoradiography
  • Fluorine-18
  • Human
  • Kinetics
  • Metabolites
  • Monkey
  • Monoamine oxidase (MAO)
  • PET

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity. / Nag, S.; Kettschau, G.; Heinrich, T.; Varrone, A.; Lehmann, L.; Gulyas, B.; Thiele, A.; Keller, E.; Halldin, C.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 1, 01.01.2013, p. 186-195.

Research output: Contribution to journalArticle

Nag, S. ; Kettschau, G. ; Heinrich, T. ; Varrone, A. ; Lehmann, L. ; Gulyas, B. ; Thiele, A. ; Keller, E. ; Halldin, C. / Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 1. pp. 186-195.
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T1 - Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity

AU - Nag, S.

AU - Kettschau, G.

AU - Heinrich, T.

AU - Varrone, A.

AU - Lehmann, L.

AU - Gulyas, B.

AU - Thiele, A.

AU - Keller, E.

AU - Halldin, C.

PY - 2013/1/1

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N2 - The aim of this project was to synthesize and evaluate three novel fluorine-18 labeled derivatives of propargyl amine as potential PET radioligands to visualize monoamine oxidase B (MAO-B) activity. The three fluorinated derivatives of propargyl amine ((S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)-pent- 4-en-2-amine (5), (S)-N-(1-fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn- 1-amine (10) and (S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine (15)) were synthesized in multi-step organic syntheses. IC50 values for inhibition were determined for compounds 5, 10 and 15 in order to determine their specificity for binding to MAO-B. Compound 5 inhibited MAO-B with an IC50 of 664 ± 48.08 nM. No further investigation was carried out with this compound. Compound 10 inhibited MAO-B with an IC50 of 208.5 ± 13.44 nM and compound 15 featured an IC50 of 131.5 ± 0.71 nM for its MAO-B inhibitory activity. None of the compounds inhibited MAO-A activity (IC50 > 2 μM). The fluorine-18 labeled analogues of the two higher binding affinity compounds (10 and 15) (S)-N-(1-[18F]fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn-1- amine (16) and (S)-1-[18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan- 2-amine (18) were both prepared from the corresponding precursors 9A, 9B and 14A, 14B by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography experiments on human postmortem brain tissue sections were performed with 16 and 18. Only compound 18 demonstrated a high selectivity for MAO-B over MAO-A and was, therefore, chosen for further examination by PET in a cynomolgus monkey. The initial uptake of 18 in the monkey brain was 250% SUV at 4 min post injection. The highest uptake of radioactivity was observed in the striatum and thalamus, regions with high MAO-B activity, whereas lower levels of radioactivity were detected in the cortex and cerebellum. The percentage of unchanged radioligand 18 was 30% in plasma at 90 min post injection. In conclusion, compound 18 is a selective inhibitor of MAO-B in vitro and demonstrated a MAO-B specific binding pattern in vivo by PET in monkey. It can, therefore, be considered as a candidate for further investigation in human by PET.

AB - The aim of this project was to synthesize and evaluate three novel fluorine-18 labeled derivatives of propargyl amine as potential PET radioligands to visualize monoamine oxidase B (MAO-B) activity. The three fluorinated derivatives of propargyl amine ((S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)-pent- 4-en-2-amine (5), (S)-N-(1-fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn- 1-amine (10) and (S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine (15)) were synthesized in multi-step organic syntheses. IC50 values for inhibition were determined for compounds 5, 10 and 15 in order to determine their specificity for binding to MAO-B. Compound 5 inhibited MAO-B with an IC50 of 664 ± 48.08 nM. No further investigation was carried out with this compound. Compound 10 inhibited MAO-B with an IC50 of 208.5 ± 13.44 nM and compound 15 featured an IC50 of 131.5 ± 0.71 nM for its MAO-B inhibitory activity. None of the compounds inhibited MAO-A activity (IC50 > 2 μM). The fluorine-18 labeled analogues of the two higher binding affinity compounds (10 and 15) (S)-N-(1-[18F]fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn-1- amine (16) and (S)-1-[18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan- 2-amine (18) were both prepared from the corresponding precursors 9A, 9B and 14A, 14B by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography experiments on human postmortem brain tissue sections were performed with 16 and 18. Only compound 18 demonstrated a high selectivity for MAO-B over MAO-A and was, therefore, chosen for further examination by PET in a cynomolgus monkey. The initial uptake of 18 in the monkey brain was 250% SUV at 4 min post injection. The highest uptake of radioactivity was observed in the striatum and thalamus, regions with high MAO-B activity, whereas lower levels of radioactivity were detected in the cortex and cerebellum. The percentage of unchanged radioligand 18 was 30% in plasma at 90 min post injection. In conclusion, compound 18 is a selective inhibitor of MAO-B in vitro and demonstrated a MAO-B specific binding pattern in vivo by PET in monkey. It can, therefore, be considered as a candidate for further investigation in human by PET.

KW - Autoradiography

KW - Fluorine-18

KW - Human

KW - Kinetics

KW - Metabolites

KW - Monkey

KW - Monoamine oxidase (MAO)

KW - PET

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