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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

Correspondence: For correspondence or reprints contact: Ana M. Catafau, MD, Centre for Imaging in Psychiatry, GlaxoSmithKline, Psychiatry CEDD, Torre Mapfre, Villa Olimpica, La Marina, 16-18, Pl. 9 B y C, 08005–Barcelona, Spain. E-mail: ana.m.catafau{at}gsk.com

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-HT_2A), 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-HT_2A receptors and its use as a SPECT ligand for measurements of drug-induced 5-HT_2A receptor occupancy in humans.

Key Words: ketanserin • neurotransmission • SPECT • ¹²³I-R91150 • 5-HT_2A

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				A. M. Catafau, M. Danus, S. Bullich, J. Llop, J. Perich, V. J. Cunningham, P. Plaza, M. M. Penengo, J. L.H. Eersels, L. Squassante, et al. Characterization of the SPECT 5-HT2A Receptor Ligand 123I-R91150 in Healthy Volunteers: Part 1--Pseudoequilibrium Interval and Quantification Methods J. Nucl. Med., June 1, 2006; 47(6): 919 - 928. [Abstract] [Full Text] [PDF]