Part 2—Ketanserin Displacement

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 be- tween ketanserin plasma concentrations and 123I-R91150 dis- placement, and the suitability of the cerebellum as a reference region for quantification. Methods: Dynamic SPECT was per- formed on 6 healthy men (mean age 6 SD, 21 6 0.89 y) from the time of 123I-R91150 injection until 470 min afterward. Ketan- serin was administered intravenously at 210 min after injection at 3 doses: 0.1 mg/kg (n 5 2), 0.05 mg/kg (n 5 2), and 0.015 mg/kg (n 5 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 draw- ing on cortical regions and cerebellum. The simplified reference tissuemodel(SRTM)wasconsideredthegoldstandardforquan- tification, and results were compared with those obtained with the tissue ratio method (TR). The percentage 123I-R91150 dis- placement 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%and71.9%-101.2%,respectively,forthe0.1mg/kgdose; 51.7%291.4% and 56.7%2102.8%, respectively, for the 0.05 mg/kg dose; and 7.7%254.5% and 13.8%247.0%, respec- tively, for the lowest dose, 0.015 mg/kg. A good correlation was found between the 2 methods. No ketanserin-induced dis- placement 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 con- centration fit with a rectangular hyperbola, with a 5.6 ng/mL con- centration 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-HT2A receptors. These results support the selectivity of 123I-R91150 for 5-HT2A receptors and its use as a SPECT ligand for measure- ments of drug-induced 5-HT2A receptor occupancy in humans.