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Characterization of the SPECT 5-HT_2A Receptor Ligand ¹²³I-R91150 in Healthy Volunteers: Part 2—Ketanserin Displacement

¹ Experimental Medical Sciences, Clinical Pharmacology Discovery Medicine, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Barcelona, Spain; ² Centre for Imaging in Psychiatry, CRC-Mar, Hospital del Mar, Barcelona, Spain; ³ Clinical Pharmacokinetics Modelling and Simulation, Psychiatry, Clinical Pharmacology Discovery Medicine, Verona, Italy; ⁴ Radiochemistry Laboratory, Institut d'Alta Tecnologia, PRBB-Fundació Privada, Barcelona, Spain; ⁵ Clinical Pharmacology Unit, IMIM, UAB, Barcelona, Spain; ⁶ Translational Medicine and Genetics, GlaxoSmithKline, Cambridge, United Kingdom; ⁷ Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, The Netherlands; and ⁸ Nuclear Medicine Department, Hospital Clinic, Barcelona, Spain

View larger version (17K): [in a new window]   FIGURE 1.  Average values for activity corresponding to unmetabolized parent compound in plasma as function of time for 0.05, 0.015, and 0.1 mg of ketanserin per kilogram for entire study (A), first 30 min after injection (B), and 70–470 min after injection (C). All values are decay corrected to injection time and normalized with injected activity. Values in A include SD.

View larger version (15K): [in a new window]   FIGURE 2.  Scatterplots of SRTM vs. TR measurements: BPpre vs. SUR180 (A), BPpost vs. SUR400 (B), and %DisplSRTM vs. %DisplTR (C).

View larger version (68K): [in a new window]   FIGURE 3.  Coregistered MRI/SPECT images from 3 representative healthy volunteers, each receiving a different ketanserin dose. Baseline scans at 180 min after injection are on left; postketanserin scans at 400 min after injection are on right. Ketanserin doses are 0.015 mg/kg (A), 0.05 mg/kg (B), and 0.1 mg/kg (C). Gradual dose-dependent displacement is seen. (Reprinted from (9 [Fig. 19]) with the kind permission of Springer Science and Business Media.)

View larger version (13K): [in a new window]   FIGURE 4.  Mean SUR values over time for all cerebral regions studied from each pair of subjects on same ketanserin dose.

View larger version (13K): [in a new window]   FIGURE 5.  Time–activity curves of cerebellum and occipital calcarine region, with corresponding SRTM fit, from subject receiving highest ketanserin dose, 0.1 mg/kg. Slight and transient decrease in cerebellum uptake is seen from 210 to 240 min, when largest decrease in cortical time–activity curve occurred. Cerebellum slope recovered completely by 270 min.

View larger version (18K): [in a new window]   FIGURE 6.  Relationship between ketanserin plasma concentration and 123I-R91150 displacement using SRTM, for all cortical regions (A); using TR, for all cortical regions (B); and comparing model fit for both SRTM and TR in representative region (prefrontal cortex) (C).