Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter

Mitchell Quinlivan, Filomena Mattner, Vahan Papazian, Jia Zhou, Andrew Katsifis, Patrick Emond, Sylvie Chalon, Alan Kozikowski, Denis Guilloteau, Michael Kassiou

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The tricyclic tropane analogues (1S,3S,6R,10S)-(Z)-10-(benzoyloxymethyl)-9-(3-chloro-4-iodobenzylidene) -7-azatricyclo[4.3.1.03,7]decane, 1, and (1S,3S,6R,10S)-(Z)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0 3,7]decane-10-carboxylic acid methyl ester, 2, have been shown to be potent and selective serotonin transporter (SERT) ligands. They possess nanomolar affinity for the SERT (Ki = 0.06 nM and 1.8 nM respectively) and are suitable for radiolabelling using iodine-123. In the present study we prepared [123I]1 and [123I]2 from the appropriate tributylstannane precursors using acidic media with chloramine-T as the oxidising agent. The radiochemical yield obtained for [123I]1 varied between 50-60% while for [123I]2 the range was 65-80%. Both radioligands were obtained with radiochemical purity > 97% and specific activity estimated to be > 185 GBq/μmol. The biodistribution of [123I]1 demonstrated low degree of brain penetration at 5 min (0.14%ID/g) with a homogenous distribution. The radioactivity cleared quickly from all brain regions with no preferential localization. In comparison, [123I]2 demonstrated on average a higher brain uptake at 5 min (0.5%ID/g). However the distribution of radioactivity was homogenous and cleared to levels similar to [123I] 1 at 1 hr post-injection. Pre-administration of citalopram failed to show any significant inhibition of [123I]2 uptake in the rat brain. The high lipophilicity of 1 and 2 (HPLC-derived log P7.4 values of 6.41 and 4.25 respectively) and in vivo metabolism, seen by high thyroid uptake would explain the absence of any specific binding observed in the rat brain. In view of these results [123I]1 and [123I]2 do not appear to be suitable radioligands for in vivo studies of the SERT.

Original languageEnglish (US)
Pages (from-to)741-746
Number of pages6
JournalNuclear Medicine and Biology
Volume30
Issue number7
DOIs
StatePublished - Oct 2003
Externally publishedYes

Fingerprint

Tropanes
Serotonin Plasma Membrane Transport Proteins
Iodine
Brain
Radioactivity
Citalopram
Carboxylic Acids
Oxidants
Thyroid Gland
Esters
High Pressure Liquid Chromatography
Ligands
Injections

Keywords

  • Iodine-123
  • Serotonin transporter
  • SPECT
  • Tricyclic tropanes

ASJC Scopus subject areas

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

Cite this

Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter. / Quinlivan, Mitchell; Mattner, Filomena; Papazian, Vahan; Zhou, Jia; Katsifis, Andrew; Emond, Patrick; Chalon, Sylvie; Kozikowski, Alan; Guilloteau, Denis; Kassiou, Michael.

In: Nuclear Medicine and Biology, Vol. 30, No. 7, 10.2003, p. 741-746.

Research output: Contribution to journalArticle

Quinlivan, M, Mattner, F, Papazian, V, Zhou, J, Katsifis, A, Emond, P, Chalon, S, Kozikowski, A, Guilloteau, D & Kassiou, M 2003, 'Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter', Nuclear Medicine and Biology, vol. 30, no. 7, pp. 741-746. https://doi.org/10.1016/S0969-8051(03)00076-3
Quinlivan, Mitchell ; Mattner, Filomena ; Papazian, Vahan ; Zhou, Jia ; Katsifis, Andrew ; Emond, Patrick ; Chalon, Sylvie ; Kozikowski, Alan ; Guilloteau, Denis ; Kassiou, Michael. / Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter. In: Nuclear Medicine and Biology. 2003 ; Vol. 30, No. 7. pp. 741-746.
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AU - Quinlivan, Mitchell

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AU - Zhou, Jia

AU - Katsifis, Andrew

AU - Emond, Patrick

AU - Chalon, Sylvie

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AU - Kassiou, Michael

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N2 - The tricyclic tropane analogues (1S,3S,6R,10S)-(Z)-10-(benzoyloxymethyl)-9-(3-chloro-4-iodobenzylidene) -7-azatricyclo[4.3.1.03,7]decane, 1, and (1S,3S,6R,10S)-(Z)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0 3,7]decane-10-carboxylic acid methyl ester, 2, have been shown to be potent and selective serotonin transporter (SERT) ligands. They possess nanomolar affinity for the SERT (Ki = 0.06 nM and 1.8 nM respectively) and are suitable for radiolabelling using iodine-123. In the present study we prepared [123I]1 and [123I]2 from the appropriate tributylstannane precursors using acidic media with chloramine-T as the oxidising agent. The radiochemical yield obtained for [123I]1 varied between 50-60% while for [123I]2 the range was 65-80%. Both radioligands were obtained with radiochemical purity > 97% and specific activity estimated to be > 185 GBq/μmol. The biodistribution of [123I]1 demonstrated low degree of brain penetration at 5 min (0.14%ID/g) with a homogenous distribution. The radioactivity cleared quickly from all brain regions with no preferential localization. In comparison, [123I]2 demonstrated on average a higher brain uptake at 5 min (0.5%ID/g). However the distribution of radioactivity was homogenous and cleared to levels similar to [123I] 1 at 1 hr post-injection. Pre-administration of citalopram failed to show any significant inhibition of [123I]2 uptake in the rat brain. The high lipophilicity of 1 and 2 (HPLC-derived log P7.4 values of 6.41 and 4.25 respectively) and in vivo metabolism, seen by high thyroid uptake would explain the absence of any specific binding observed in the rat brain. In view of these results [123I]1 and [123I]2 do not appear to be suitable radioligands for in vivo studies of the SERT.

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