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Pharmacological evaluation of [123I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS)

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The study aims to evaluate the iodinated imidazopyridine, N′,N′-diethyl-6-Chloro-(4′-[123I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide ([123I]-CLINDE) as a tracer for the study of peripheral benzodiazepine binding sites (PBBS).

Materials and methods

In vitro studies were performed using membrane homogenates and sections from kidney, adrenals, and brain cortex of Sprague-Dawley (SD) rats and incubated with [123I]-CLINDE. For in vivo studies, the rats were injected with [123I]-CLINDE. In competition studies, PBBS-specific drugs PK11195 and Ro 5-4864 and the CBR specific drug Flumazenil were injected before the radiotracer.

Results

In vitro binding studies in adrenal, kidney, and cortex mitochondrial membranes indicated that [123I]-CLINDE binds with high affinity to PBBS, K d = 12.6, 0.20, and 3.84 nM, respectively. The density of binding sites was 163, 5.3, and 0.34 pmol/mg protein, respectively. In vivo biodistribution indicated high uptake in adrenals (5.4), heart (1.5), lungs (1.5), kidney (1.5) %ID/g at 6 h p.i. In the central nervous system (CNS), the olfactory bulbs displayed the highest uptake; up to six times the activity in blood. Pre-administration of unlabeled CLINDE, PK11195 and Ro 5-4864 (1 mg/kg) reduced the uptake of [123I]-CLINDE by 70-55% in olfactory bulbs. In the kidney and heart, a reduction of 60-80% ID/g was observed, while an increase was observed in the adrenals requiring 10 mg/kg for significant displacement. Flumazenil had no effect on uptake in peripheral organs and brain. Metabolite analysis indicated >90% of the radioactivity in the above tissues was intact [123I]-CLINDE.

Conclusion

[123I]-CLINDE displays high and selective uptake for the PBBS and warrants further development as a probe for imaging PBBS using single photon emission computed tomography (SPECT).

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Acknowledgements

The authors wish to thank Dr. Christian Loc’h for assistance with the preparation of the manuscript. The authors also thank Janette Chapman and Kerrynne Belbin for the assistance with the in vivo studies.

All in vivo experimental procedures were carried out in compliance with Australian laws governing animal experimentation.

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Authors and Affiliations

  1. Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, PMB 1 Menai, N.S.W., 2234, Sydney, Australia

    Filomena Mattner & Andrew Katsifis

  2. Centre for Studies in Drug Disposition, The University of Queensland, Clinical Sciences Building, Royal Brisbane Hospital, QLD 4029, Brisbane, Australia

    Karine Mardon

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  1. Filomena Mattner
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Correspondence to Filomena Mattner.

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Mattner, F., Mardon, K. & Katsifis, A. Pharmacological evaluation of [123I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS). Eur J Nucl Med Mol Imaging 35, 779–789 (2008). https://doi.org/10.1007/s00259-007-0645-5

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