Karina H Vase1, Dan Peters2, Elsebet Ø Nielsen3, Aage K O Alstrup4, Dirk Bender4. 1. PET Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. Electronic address: karina@pet.auh.dk. 2. DanPET AB, Rosenstigen 7, SE-216 19 Malmö, Sweden. 3. NeuroSearch A/S, Pederstrupsvej 93, DK-2750 Ballerup, Denmark. 4. PET Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Abstract
INTRODUCTION: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [(11)C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [(11)C]methanolate in a Boc-protected precursor. The isolated [(11)C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[(11)C]-O-methylreboxetine ([(11)C]MeNER). RESULTS: The radiolabeling technique yielded [(11)C]NS8880 in low (<10%) but still useful yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [(11)C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [(11)C]NS8880. CONCLUSION: Based on the pre-clinical results obtained so far [(11)C]NS8880 displays promising properties for PET imaging of NET.
INTRODUCTION: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [(11)C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [(11)C]methanolate in a Boc-protected precursor. The isolated [(11)C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[(11)C]-O-methylreboxetine ([(11)C]MeNER). RESULTS: The radiolabeling technique yielded [(11)C]NS8880 in low (<10%) but still useful yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [(11)C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [(11)C]NS8880. CONCLUSION: Based on the pre-clinical results obtained so far [(11)C]NS8880 displays promising properties for PET imaging of NET.
Authors: Francisco R López-Picón; Anna K Kirjavainen; Sarita Forsback; Jatta S Takkinen; Dan Peters; Merja Haaparanta-Solin; Olof Solin Journal: Theranostics Date: 2019-01-01 Impact factor: 11.556