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Characterization of the SPECT 5-HT_2A Receptor Ligand ¹²³I-R91150 in Healthy Volunteers: Part 1—Pseudoequilibrium Interval and Quantification Methods

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 Radiochemistry Laboratory, Institut d'Alta Tecnologia, PRBB-Fundació Privada, Barcelona, Spain; ⁴ Magnetic Resonance Department, CRC-MAR, Hospital del Mar, Barcelona, Spain; ⁵ Translational Medicine and Genetics, GlaxoSmithKline, Cambridge, United Kingdom; ⁶ Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, The Netherlands; ⁷ Clinical Pharmacology Statistics and Programming, Biomedical Data Sciences, GlaxoSmithKline, Verona, Italy; ⁸ Biophysics and Bioengineering Unit, University of Barcelona, Barcelona, Spain; and ⁹ Clinical Pharmacology Unit, Hospital Sant Pau, 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

With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide (¹²³I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT_2A), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval after a single bolus injection was identified, and a reference database of specific uptake ratio (SUR) values was obtained. Within-scan and between-subject variability was also assessed. Methods: Nineteen healthy men (mean age ± SD, 24.4 ± 3.3 y) were included and separated into 2 groups. Dynamic scans with venous blood sampling from 0 to 470 min after a single bolus injection of ¹²³I-R91150 was completed for 7 of the 9 subjects included in group A, and in one of them compartmental modeling was performed with an arterial blood input function using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models. Binding potential (BP) using the simplified reference tissue model (SRTM) (BP_SRTM) and SUR values using TR over time were also calculated. The 10 remaining subjects (group B) underwent a single scan at pseudoequilibrium with the aim of improving the precision of mean normal SUR estimates. Regions of interest in cortical regions and basal ganglia for specific uptake, and in cerebellum for nonspecific uptake, were manually drawn on each subject's MR images and translated to the corresponding SPECT slices after coregistration. Results: The 1TC model correlated well with the 2TC model (BP_2TC = 1.04·BP_1TC – 0.01, R² = 0.98), and both methods correlated with BP_SRTM and SUR with little bias (BP_1TC = 1.10 BP_SRTM + 0.03, R² = 0.98; BP_2TC = 1.15 BP_SRTM + 0.01, R² = 0.98; BP_SRTM = 0.99 SUR_mean + 0.01, R² = 0.98). SUR values stabilized from 180 min after injection in most cortical regions, ranging from 0.51 ± 0.10 in the orbitofrontal region to 0.27 ± 0.09 in the parietal region. Within-scan and between-subject variability among regions ranged from 10% to 14.8%, and from 18.3% to 35.4%, respectively. Conclusion: ¹²³I-R91150 distribution agrees with autoradiography results, showing highly specific binding in cortical regions. The correlations found among 1TC, 2TC, SRTM, and TR outcome measurements support the use of TR for quantification of 5-HT_2A receptor binding with ¹²³I-R91150 SPECT and a simple protocol avoiding arterial blood sampling and serial scanning over time.

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