In vivo evaluation in rodents of [¹²³I]-3-I-CO as a potential SPECT tracer for the serotonin 5-HT_2A receptor

Abstract 

Introduction

[¹²³I]-(4-fluorophenyl)[1-(3-iodophenethyl)piperidin-4-yl]methanone ([¹²³I]-3-I-CO) is a potential single photon emission computed tomography tracer with high affinity for the serotonin 5-HT_2A receptor (K_i=0.51 nM) and good selectivity over other receptor (sub)types. To determine the potential of the radioligand as a 5-HT_2A tracer, regional brain biodistribution and displacement studies will be performed. The influence of P-glycoprotein blocking on the brain uptake of the radioligand will also be investigated.

Methods

A regional brain biodistribution study and a displacement study with ketanserin were performed with [¹²³I]-3-I-CO. Also, the influence of cyclosporin A (50 mg/kg) on the brain distribution of the radioligand was investigated. For the displacement study, ketanserin (1 mg/kg) was administered 30 min after injection of [¹²³I]-3-I-CO.

Results

The initial brain uptake of [¹²³I]-3-I-CO was quite high, but a rapid wash-out of radioactivity was observed. Cortex-to-cerebellum binding index ratios were low (1.1 – 1.7), indicating considerable aspecific binding and a low specific ‘signal’ of the radioligand. Tracer uptake was reduced to the levels in cerebellum (a 60% reduction) after ketanserin displacement. Administration of cyclosporin A resulted in a doubling of the brain radioactivity concentration.

Conclusions

Although [¹²³I]-3-I-CO showed adequate brain uptake and could be displaced by ketanserin, high aspecific binding to brain tissue was responsible for very low cortex-to-cerebellum binding index ratios, possibly limiting the potential of the radioligand as a serotonin 5-HT_2A receptor tracer. We also demonstrated that [¹²³I]-3-I-CO is probably a weak substrate for the P-glycoprotein efflux transporter.

Keywords: Serotonin, P-glycoprotein, 5-HT_2A receptor, Brain tracer