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Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

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Abstract

Purpose

Several lines of evidence imply early alterations in metabolic, dopaminergic and endocannabinoid neurotransmission in Huntington’s disease (HD). Using [18F]MK-9470 and small animal PET, we investigated cerebral changes in type 1 cannabinoid (CB1) receptor binding in the quinolinic acid (QA) rat model of HD in relation to glucose metabolism, dopamine D2 receptor availability and amphetamine-induced turning behaviour.

Methods

Twenty-one Wistar rats (11 QA and 10 shams) were investigated. Small animal PET acquisitions were conducted on a Focus 220 with approximately 18 MBq of [18F]MK-9470, [18F]FDG and [11C]raclopride. Relative glucose metabolism and parametric CB1 receptor and D2 binding images were anatomically standardized to Paxinos space and analysed voxel-wise using Statistical Parametric Mapping (SPM2).

Results

In the QA model, [18F]MK-9470 uptake, glucose metabolism and D2 receptor binding were reduced in the ipsilateral caudate-putamen by 7, 35 and 77%, respectively (all p < 2.10−5), while an increase for these markers was observed on the contralateral side (>5%, all p < 7.10−4). [18F]MK-9470 binding was also increased in the cerebellum (p = 2.10−5), where it was inversely correlated to the number of ipsiversive turnings (p = 7.10−6), suggesting that CB1 receptor upregulation in the cerebellum is related to a better functional outcome. Additionally, glucose metabolism was relatively increased in the contralateral hippocampus, thalamus and sensorimotor cortex (p = 1.10−6).

Conclusion

These data point to in vivo changes in endocannabinoid transmission, specifically for CB1 receptors in the QA model, with involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum. These data also indicate the occurrence of functional plasticity on metabolism, D2 and CB1 neurotransmission in the contralateral hemisphere.

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Acknowledgements

Merck & Co., Inc. is acknowledged for the availability of the [18F]MK-9470 precursor, and for their critical revision of this manuscript and their improving suggestions. The authors thank Peter Vermaelen for his assistance in data acquisition, as well as the Leuven PET radiopharmacy team for tracer preparations. Financial support of the Research Council of the Katholieke Universiteit Leuven (OT/05/58), the Fund for Scientific Research, Flanders, Belgium (FWO/G.0548.06), the K.U. Leuven Molecular Small Animal Imaging Center (KUL EF/05/08), and the Institute for the Promotion of Innovation by Science and Technology in Flanders (SBO50151) is gratefully acknowledged. Part of this work is also performed under the European Commission FP6 project Diagnostic Molecular Imaging (DIMI), LSHB-CT-2005-512146.

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Authors and Affiliations

  1. Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Leuven, Belgium

    Cindy Casteels & Koen Van Laere

  2. MoSAIC, Molecular Small Animal Imaging Center, KU Leuven, Leuven, Belgium

    Cindy Casteels, Guy Bormans & Koen Van Laere

  3. Institute for Biomedical Research (IIBB-CSIC), IDIBAPS, Barcelona, Spain

    Emili Martinez, Lluïsa Camon, Núria de Vera & Anna M. Planas

  4. Laboratory for Radiopharmacy, KU Leuven, Leuven, Belgium

    Guy Bormans

  5. Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium

    Veerle Baekelandt

  6. Division of Nuclear Medicine, University Hospital Gasthuisberg, Herestraat 49 bus 7003, 3000, Leuven, Belgium

    Cindy Casteels

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  1. Cindy Casteels
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Correspondence to Cindy Casteels.

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Casteels, C., Martinez, E., Bormans, G. et al. Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism. Eur J Nucl Med Mol Imaging 37, 2354–2363 (2010). https://doi.org/10.1007/s00259-010-1574-2

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