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Synthesis and Preliminary Evaluation of Piperidinyl and Pyrrolidinyl Iodobenzoates as Imaging Agents for Butyrylcholinesterase

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Abstract

Purpose

The purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer’s disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain.

Procedures

Iodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding 123I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system.

Results

The three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with 123I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation.

Conclusion

BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.

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Acknowledgments

The Canadian Institutes of Health Research (MOP-82798), Canadian Institutes of Health Research Vascular Health and Dementia Initiative (DOV-78344) (through partnership of Canadian Institutes of Health Research, Heart & Stroke Foundation of Canada, the Alzheimer Society of Canada and Pfizer Canada Inc.), Capital District Health Authority Research Fund, Nova Scotia Health Research Foundation, National Sciences and Engineering Research Council, Canadian Foundation for Innovation, Dalhousie Radiology Research Foundation, Dalhousie University, and Mount Saint Vincent University are gratefully acknowledged. We thank Amy Morris, Marlene Hudgins, Melissa Morash, Anita Macdonald, Simone LaForest, and Eva Rogerson for their technical assistance.

Conflict of Interest Disclosure

Application for patent protection has been filed relating to the iodobenzoate esters described in this manuscript, through Treventis Corporation, in which one of the authors (SD) is a shareholder. SD made an invited presentation (possible mechanisms underlying effects of BuChE—emerging hypotheses to spark future research) at a mini-symposium entitled “Emerging hypotheses in cholinesterase inhibition: targeted activity for optimal effects”, organized by Novartis in Geneva as part of the 11th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy. No funding has been received from either of these companies in support of the work described herein.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology and the Neuroscience Institute, Dalhousie University, Halifax, NS, B3H 1X5, Canada

    Ian R. Macdonald, G. Andrew Reid & Sultan Darvesh

  2. Department of Chemistry and Physics, Mount Saint Vincent University, Halifax, Nova Scotia, B3M 2J6, Canada

    E. Eric Joy, Ian R. Pottie, Earl Martin & Sultan Darvesh

  3. Department of Chemistry, Saint Mary’s University, Halifax, Nova Scotia, B3H 3C3, Canada

    Ian R. Pottie

  4. Department of Radiology, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada

    Gilbert Matte, Steven Burrell & George Mawko

  5. Department of Medicine (Neurology and Geriatric Medicine), Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada

    Sultan Darvesh

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  1. Ian R. Macdonald
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Correspondence to Sultan Darvesh.

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Macdonald, I.R., Reid, G.A., Joy, E.E. et al. Synthesis and Preliminary Evaluation of Piperidinyl and Pyrrolidinyl Iodobenzoates as Imaging Agents for Butyrylcholinesterase. Mol Imaging Biol 13, 1250–1261 (2011). https://doi.org/10.1007/s11307-010-0448-0

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