Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor α7 subtype imaging agent

Ogawa, Mikako; Tatsumi, Ryo; Fujio, Masakazu; Katayama, Jiro; Magata, Yasuhiro

doi:10.1016/j.nucmedbio.2005.12.016

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 3 , Pages 311-316, April 2006

Synthesis and evaluation of [¹²⁵I]I-TSA as a brain nicotinic acetylcholine receptor α₇ subtype imaging agent

Mikako Ogawa
- Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192, Japan
Ryo Tatsumi
- Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan
Masakazu Fujio
- Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan
Jiro Katayama
- Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan
Yasuhiro Magata
- Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192, Japan
- Corresponding author. Tel.: +81 53 435 2398; fax: +81 53 435 2398.

Received 9 November 2005; received in revised form 20 December 2005; accepted 26 December 2005. published online 13 March 2006.

Abstract

Introduction

Some in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) α₇ subtype is implicated in Alzheimer's disease, schizophrenia and others. Recently, we developed (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5′-[1′,3′]oxazolidin]-2′-one (Br-TSA), which has a high affinity and selectivity for α₇ nAChRs. Therefore we synthesized (R)-3′-(5-[¹²⁵I]iodothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5′-[1′,3′]oxazolidin]-2′-one ([¹²⁵I]I-TSA) and evaluated its potential for the in vivo detection of α₇ nAChR in brain.

Methods

In vitro binding affinity of I-TSA was measured in rat brain homogenates. Radioiodination was accomplished by a Br-I exchange reaction. Biodistribution studies were undertaken in mice by tail vein injection of [¹²⁵I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 μl, i.c.v.) or nonradioactive I-TSA (50 μmol/kg, i.v.).

Results

I-TSA exhibited a high affinity and selectivity for the α₇ nAChR (K_i for α₇ nAChR=0.54 nM). Initial uptake in the brain was high (4.42 %dose/g at 5 min), and the clearance of radioactivity was relatively slow in the hippocampus (α₇ nAChR-rich region) and was rather rapid in the cerebellum (α₇ nAChR poor region). The hippocampus to cerebellum uptake ratio was 0.9 at 5 min postinjection, but it was increased to 1.8 at 60 min postinjection. Although the effect was not statistically significant, administration of I-TSA and MLA decreased the accumulation of radioactivity in hippocampus.

Conclusion

Despite its high affinity and selectivity, [¹²⁵I]I-TSA does not appear to be a suitable tracer for in vivo α₇ nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed.

Keywords: [¹²⁵I]I-TSA, Nicotinic acetylcholine receptor α₇ subtype, Central nervous system, Radiosynthesis, In vivo evaluation