TY - JOUR
T1 - Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter
AU - Quinlivan, Mitchell
AU - Mattner, Filomena
AU - Papazian, Vahan
AU - Zhou, Jia
AU - Katsifis, Andrew
AU - Emond, Patrick
AU - Chalon, Sylvie
AU - Kozikowski, Alan
AU - Guilloteau, Denis
AU - Kassiou, Michael
N1 - Funding Information:
This study was supported in part by the France-Australia collaboration in Nuclear Medicine and Biology and the Australian Institute of Nuclear Science and Engineering (Grant ID 605).
PY - 2003/10
Y1 - 2003/10
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.
AB - 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.
KW - Iodine-123
KW - SPECT
KW - Serotonin transporter
KW - Tricyclic tropanes
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U2 - 10.1016/S0969-8051(03)00076-3
DO - 10.1016/S0969-8051(03)00076-3
M3 - Article
C2 - 14499332
AN - SCOPUS:10744226409
SN - 0969-8051
VL - 30
SP - 741
EP - 746
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 7
ER -