Improved synthesis of [ 18 F] fallypride and characterization of a Huntington's disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors.

Autor: Huhtala T; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland. tuulia.huhtala@crl.com., Poutiainen P; Department of Neurobiology, A.I. Virtanen Institute for Molecular Medicine, University of Eastern Finland, 70211, Kuopio, Finland.; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, 70210, Kuopio, Finland., Rytkönen J; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland., Lehtimäki K; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland., Parkkari T; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland., Kasanen I; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland., Airaksinen AJ; Department of Chemistry - Radiochemistry, University of Helsinki, 00014, Helsinki, Finland., Koivula T; Department of Chemistry - Radiochemistry, University of Helsinki, 00014, Helsinki, Finland., Sweeney P; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland., Kontkanen O; Charles River Discovery Services, Microkatu 1, 70210, Kuopio, Finland., Wityak J; CHDI Management/CHDI Foundation, Los Angeles, CA, USA., Dominiquez C; CHDI Management/CHDI Foundation, Los Angeles, CA, USA., Park LC; CHDI Management/CHDI Foundation, Los Angeles, CA, USA. larryparkhd@gmail.com.
Jazyk: angličtina
Zdroj: EJNMMI radiopharmacy and chemistry [EJNMMI Radiopharm Chem] 2019 Aug 05; Vol. 4 (1), pp. 20. Date of Electronic Publication: 2019 Aug 05.
DOI: 10.1186/s41181-019-0071-6
Abstrakt: Purpose: Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington's disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [ 18 F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [ 18 F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD.
Methods: We longitudinally characterized in vivo [ 18 F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12 month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [ 3 H] fallypride autoradiography at 12 months of age.
Results: We implemented an improved synthesis method for [ 18 F] fallypride to yield high molar activity (MA, 298-360 GBq/μmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BP ND ) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to WT littermates. No mass effect was observed when the MA of [ 18 F] fallypride was > 100 GBq/μmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [ 3 H] fallypride autoradiography.
Conclusions: We observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12 months of age. These results are in line with clinical findings in HD patients, suggesting [ 18 F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.
Databáze: MEDLINE
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