As part of the radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)-propyl]-4- methyl-4-piperidinyl]5-iodo-2-methoxybenzamide (123I-R91150) characterization study, ketanserin challenges were performed on healthy volunteers with the aim of assessing the specificity of 123I-R91150 binding to subtype 2A of the 5-hydroxytryptamine receptor (5-HT2A), the sensitivity of 123I-R91150 SPECT in measuring ligand displacement, the relationship between ketanserin plasma concentrations and 123I-R91150 displacement, and the suitability of the cerebellum as a reference region for quantification. Methods: Dynamic SPECT was performed on 6 healthy men (mean age ± SD, 21 ± 0.89 y) from the time of 123I-R91150 injection until 470 min afterward. Ketanserin was administered intravenously at 210 min after injection at 3 doses: 0.1 mg/kg (n = 2), 0.05 mg/kg (n = 2), and 0.015 mg/kg (n = 2). Blood samples for measurement of ketanserin plasma concentrations were drawn. MRI was performed on all subjects and coregistered to the SPECT data for region-of-interest drawing on cortical regions and cerebellum. The simplified reference tissue model (SRTM) was considered the gold standard for quantification, and results were compared with those obtained with the tissue ratio method (TR). The percentage 123I-R91150 displacement was calculated with both methods as the percentage difference between baseline and postketanserin scans. Results: Depending on the cerebral regions with the maximum ketanserin dose studied, SRTM and TR mean displacements were 57.1%-95.4% and 71.9%-101.2%, respectively, for the 0.1 mg/kg dose; 51.7%-91.4% and 56.7%-102.8%, respectively, for the 0.05 mg/kg dose; and 7.7%-54.5% and 13.8%-47.0%, respectively, for the lowest dose, 0.015 mg/kg. A good correlation was found between the 2 methods. No ketanserin-induced displacement was observed in the cerebellum time-activity curves, supporting the use of the cerebellum as a reference region. The relationship between displacement and ketanserin plasma concentration fit with a rectangular hyperbola, with a 5.6 ng/mL concentration associated with 50% of the maximum displacement (EC50). EC50 values calculated using occupancies derived both with SRTM and with TR were in good agreement. Conclusion: 123I-R91150 SPECT is sensitive enough to measure ketanserin dose-dependent displacement in cerebral regions rich in 5-HT 2A receptors. These results support the selectivity of 123I-R91150 for 5-HT2A receptors and its use as a SPECT ligand for measurements of drug-induced 5-HT2A receptor occupancy in humans.
|Journal||Journal of Nuclear Medicine|
|Publication status||Published - 1 Dec 2006|
- 5-HT 2A
- 123 I-R91150