Sergio Estrada1, Mark Lubberink2, Alf Thibblin3, Margareta Sprycha4, Tim Buchanan5, Nathalie Mestdagh5, Benoit Kenda5, Joel Mercier5, Laurent Provins5, Michel Gillard5, Dominique Tytgat5, Gunnar Antoni6. 1. Preclinical PET platform, Uppsala University, Uppsala, Sweden. 2. Nuclear Medicine & PET, Uppsala University, Uppsala, Sweden; Medical Physics, Uppsala University Hospital, Uppsala, Sweden. 3. Nuclear Medicine & PET, Uppsala University, Uppsala, Sweden; PET Centre, Uppsala University Hospital, Uppsala, Sweden. 4. PET Centre, Uppsala University Hospital, Uppsala, Sweden. 5. UCB Pharma, Brussels, Belgium. 6. Preclinical PET platform, Uppsala University, Uppsala, Sweden; PET Centre, Uppsala University Hospital, Uppsala, Sweden. Electronic address: gunnar.antoni@pet.medchem.uu.se.
Abstract
INTRODUCTION: Development of a selective and specific high affinity PET tracer, [(11)C]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine VT. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. RESULTS: 3-5GBq of [(11)C]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65GBq/μmol. In vitro binding showed high selective binding towards SV2A. [(11)C]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the VT could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [(11)C]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. CONCLUSIONS: We have developed the novel PET tracer, [(11)C]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400MBq of [(11)C]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline VT values. This will have to be further validated in human studies.
INTRODUCTION: Development of a selective and specific high affinity PET tracer, [(11)C]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine VT. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. RESULTS: 3-5GBq of [(11)C]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65GBq/μmol. In vitro binding showed high selective binding towards SV2A. [(11)C]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the VT could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [(11)C]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. CONCLUSIONS: We have developed the novel PET tracer, [(11)C]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400MBq of [(11)C]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline VT values. This will have to be further validated in human studies.
Authors: Stefanie M A Willekens; Donatienne Van Weehaeghe; Philip Van Damme; Koen Van Laere Journal: Eur J Nucl Med Mol Imaging Date: 2016-12-08 Impact factor: 9.236
Authors: Samantha Rossano; Takuya Toyonaga; Sjoerd J Finnema; Mika Naganawa; Yihuan Lu; Nabeel Nabulsi; Jim Ropchan; Steven De Bruyn; Christian Otoul; Armel Stockis; Jean-Marie Nicolas; Paul Martin; Joel Mercier; Yiyun Huang; R Paul Maguire; Richard E Carson Journal: J Cereb Blood Flow Metab Date: 2019-09-30 Impact factor: 6.200