Synthesis and Biological Evaluation of 125I/123I-Labelled Analogues of Citalopram and Escitalopram as Potential Radioligands for Imaging of the Serotonin Transporter

TY - JOUR

T1 - Synthesis and Biological Evaluation of 125I/123I-Labelled Analogues of Citalopram and Escitalopram as Potential Radioligands for Imaging of the Serotonin Transporter

AU - Madsen, Jacob

AU - Elfving, Betina

AU - Frøkjær, Vibe

AU - Kornum, Birgitte R.

AU - Thomsen, Gerda

AU - Martiny, Lars

AU - Knudsen, Gitte Moos

PY - 2011/4

Y1 - 2011/4

N2 - Two novel radioligands for the serotonin transporter (SERT), [ 125I]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl] -propyl}-dimethylamine ([125I]-2) and S-[125I]{3-[5-iodo- 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([ 125I]-(S)-2) were synthesized in a Br/125I exchange reaction. Binding experiments in rats yielded Kd values of 0.7 ± 0.06 and 0.52± 0.02 nM for [125I]-2 and [ 125I]-(S)-2, respectively. One hour after intravenous injection of [125I]-2, 0.34% of the injected dose had accumulated in the brain. The highest hypothalamus-to-cerebellum ratio was reached 2 h after injection of [125I]-(S)-2 and amounted to 2.4. Pre-treatment experiments with paroxetine resulted in effective reduction of the target-to-cerebellum ratios. The corresponding iodine-123 labelled compound S-[123I]{3-[5-Iodo-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine [ 123I]-S-2 was investigated in a pig single photon emission computed tomography (SPECT) study. Between 60 and 110 min after IV injection, the midbrain-to-cerebellum ratio was 1.2. However, the uptake did not differ between high-density and medium-density regions questioning the feasibility of the radioligand in imaging cortical SERT distribution in vivo. These data suggest that the iodine-labelled derivatives of citalopram and escitalopram are not superior to another SPECT tracer for the SERT, namely [123I]ADAM.

AB - Two novel radioligands for the serotonin transporter (SERT), [ 125I]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl] -propyl}-dimethylamine ([125I]-2) and S-[125I]{3-[5-iodo- 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([ 125I]-(S)-2) were synthesized in a Br/125I exchange reaction. Binding experiments in rats yielded Kd values of 0.7 ± 0.06 and 0.52± 0.02 nM for [125I]-2 and [ 125I]-(S)-2, respectively. One hour after intravenous injection of [125I]-2, 0.34% of the injected dose had accumulated in the brain. The highest hypothalamus-to-cerebellum ratio was reached 2 h after injection of [125I]-(S)-2 and amounted to 2.4. Pre-treatment experiments with paroxetine resulted in effective reduction of the target-to-cerebellum ratios. The corresponding iodine-123 labelled compound S-[123I]{3-[5-Iodo-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine [ 123I]-S-2 was investigated in a pig single photon emission computed tomography (SPECT) study. Between 60 and 110 min after IV injection, the midbrain-to-cerebellum ratio was 1.2. However, the uptake did not differ between high-density and medium-density regions questioning the feasibility of the radioligand in imaging cortical SERT distribution in vivo. These data suggest that the iodine-labelled derivatives of citalopram and escitalopram are not superior to another SPECT tracer for the SERT, namely [123I]ADAM.

M3 - Journal article

SN - 0362-4803

VL - 54

SP - 185

EP - 190

JO - Journal of Labelled Compounds and Radiopharmaceuticals

JF - Journal of Labelled Compounds and Radiopharmaceuticals

ER -