- Email: [email protected]
PET imaging of the norepinephrine transporter: A review plus new developments
T136
Poster Presentations / NeuroImage 31 (2006) T44 – T186
Poster Presentation No.: 086
PET imaging of the norepinephrine transporter: A review plus new developments Yu-Shin Ding,1 K.-S. Lin 2 1
Yale University School of Medicine, USA 2 University of Pittsburgh, PA, USA
Objectives: We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with PET. Based on our extensive characterization studies, we have identified a number of reboxetine (RB) analogues that are suitable radioligands for PET studies of brain NET, including (S,S)-[11C]MRB, (S,S)-[11C]3-Cl-MRB and [18F]FERB-D4, with (S,S)-[11C]MRB being the best. (R)-[11C]Nisoxetine, [11C]oxaprotiline and [11C]lortalamine all suffer from high non-specific striatal uptake (higher than thalamus) and low S/N ratio, in spite of their high affinity and high selectivity in vitro. Our comparative studies indicate that, although there is uptake in striatum after i.v. injection of (S,S)-[11C]MRB, its striatal uptake is, by far, the least significant among all the tracers examined. Thus, we have initiated PET studies in humans with (S,S)-[11C]MRB. These results, along with many other previously reported disappointing ligands, such as [11C]desipramine and [11C]iodo-nisoxetine, suggest that analogues of MRB are still the most promising structures for further development of potential NET ligands. In search of optimal tracers for in vivo imaging of the NET system, we have prepared more new ligands, and comparative studies in baboon will be presented. Methods: Multi-step synthetic procedures were developed to prepare the corresponding precursors, which were used to synthesize C-11- and F-18-labeled NET radioligands. PET imaging studies were then carried out in baboons. Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P = 1.0 – 3.5), high plasma-free fraction and reasonable stability in plasma were selected as candidates for further studies. A critical examination of the kinetic properties of radioligands has been a crucial part of our radiotracer development strategy. Results: We have carried out human studies using (S,S)-[11C]MRB. In addition, we have synthesized and evaluated four new ligands for imaging the NET system in baboons with PET. All four new analogues of MRB have reasonable calculated log P values, and the synthetic strategies were adapted from our previous approaches to reboxetine analogues. These compounds may allow us to learn more regarding the structure – affinity relationships (SAR) of this class of compounds, especially since it has been shown that a slight modification of structure results in drastic changes in pharmacological activity. The recent development of NET ligands will be reviewed, and our results using the new ligands will be presented. Supported by DOE-OBER, ONDCP and NIH. doi:10.1016/j.neuroimage.2006.04.120
Poster Presentations / NeuroImage 31 (2006) T44 – T186
Poster Presentation No.: 086
PET imaging of the norepinephrine transporter: A review plus new developments Yu-Shin Ding,1 K.-S. Lin 2 1
Yale University School of Medicine, USA 2 University of Pittsburgh, PA, USA
Objectives: We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with PET. Based on our extensive characterization studies, we have identified a number of reboxetine (RB) analogues that are suitable radioligands for PET studies of brain NET, including (S,S)-[11C]MRB, (S,S)-[11C]3-Cl-MRB and [18F]FERB-D4, with (S,S)-[11C]MRB being the best. (R)-[11C]Nisoxetine, [11C]oxaprotiline and [11C]lortalamine all suffer from high non-specific striatal uptake (higher than thalamus) and low S/N ratio, in spite of their high affinity and high selectivity in vitro. Our comparative studies indicate that, although there is uptake in striatum after i.v. injection of (S,S)-[11C]MRB, its striatal uptake is, by far, the least significant among all the tracers examined. Thus, we have initiated PET studies in humans with (S,S)-[11C]MRB. These results, along with many other previously reported disappointing ligands, such as [11C]desipramine and [11C]iodo-nisoxetine, suggest that analogues of MRB are still the most promising structures for further development of potential NET ligands. In search of optimal tracers for in vivo imaging of the NET system, we have prepared more new ligands, and comparative studies in baboon will be presented. Methods: Multi-step synthetic procedures were developed to prepare the corresponding precursors, which were used to synthesize C-11- and F-18-labeled NET radioligands. PET imaging studies were then carried out in baboons. Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P = 1.0 – 3.5), high plasma-free fraction and reasonable stability in plasma were selected as candidates for further studies. A critical examination of the kinetic properties of radioligands has been a crucial part of our radiotracer development strategy. Results: We have carried out human studies using (S,S)-[11C]MRB. In addition, we have synthesized and evaluated four new ligands for imaging the NET system in baboons with PET. All four new analogues of MRB have reasonable calculated log P values, and the synthetic strategies were adapted from our previous approaches to reboxetine analogues. These compounds may allow us to learn more regarding the structure – affinity relationships (SAR) of this class of compounds, especially since it has been shown that a slight modification of structure results in drastic changes in pharmacological activity. The recent development of NET ligands will be reviewed, and our results using the new ligands will be presented. Supported by DOE-OBER, ONDCP and NIH. doi:10.1016/j.neuroimage.2006.04.120