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Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET

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Abstract

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT4) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT4 receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT4 receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT4 receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [123I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT4 receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT4 receptor antagonist, SB 204070, at 20 min before [123I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [123I]SB 207710 is an effective radioligand for imaging brain 5-HT4 receptors in vivo.

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Acknowledgements

The authors are grateful to Drs. L. Gaster and A.M. Brown (formerly of SmithKline Beecham Pharmaceuticals, Harlow, UK, and now of GlaxoSmithKline, Cambridge, UK) and Dr. R. Clark (Roche Biosciences, Palo Alto, California, USA) for their interest in and support of this work, and to SmithKline Beecham Pharmaceuticals for support to J.W. This work was also supported by grants from the Swedish Medical Research Council (03560 and 0914), the Swedish Natural Science Research Council (KU 9973-308), the USA National Institute of Mental Health (NIMH, 41205 and 44814), the Söderström-König Foundation and the Karolinska Institutet.

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  1. Victor W. Pike

    Present address: PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892-1003, USA

  2. Rachel S. Mulligan

    Present address: Centre for PET, Austin and Repatriation Medical Centre, Studley Road, Melbourne VIC 3084, Australia

  3. Susan P. Hume

    Present address: Imaging Research Solutions Ltd., Cyclotron Building, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK

  4. Ella Hirani

    Present address: Imaging Research Solutions Ltd., Cyclotron Building, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK

Authors and Affiliations

  1. MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK

    Victor W. Pike, Rachel S. Mulligan, Susan P. Hume, Ella Hirani & Jaqueline Whalley

  2. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, 17176, Stockholm, Sweden

    Christer Halldin, Kenji Nobuhara, Carl-Gunnar Swahn, Per Karlsson, Hans Olsson, Stig Larsson, Per-Olof Schnell & Lars Farde

  3. MAP Medical Technologies, Oy, Tikkakoski, Finland

    Julka Hiltunen

  4. Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE 8AF, UK

    Rachel S. Mulligan & Lyn S. Pilowsky

  5. Institute of Nuclear Medicine, Royal Free and University College, Medical School, Mortimer Street, London, W1N 8AA, UK

    Lyn S. Pilowsky & Peter J. Ell

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Correspondence to Victor W. Pike.

Additional information

For preliminary accounts of this work, see Pike VW et al., J Nucl Med 1998; 39 (Suppl):185; Eur J Nucl Med 1999; 26:991.

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Pike, V.W., Halldin, C., Nobuhara, K. et al. Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET. Eur J Nucl Med Mol Imaging 30, 1520–1528 (2003). https://doi.org/10.1007/s00259-003-1307-x

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