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J Nucl Med. 2008; 49 (Supplement 1):284P
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Radiopharmaceutical Chemistry: New Chemistry-Neurosciences

New Chemistry-Neurosciences Posters

Synthesis and evaluation of (S,S)-[11C]SMENET as a norepinephrine transporter imaging agent

Fanxing Zeng1, Jiyoung Mun1, Nachwa Jarkas1, Jeffrey Stehouwer1, Ronald Voll1, Larry Williams1, John Votaw1, Leonard Howell2 and Mark Goodman1

1 Radiology; 2 Yerkes Primate Center, Emory University, Atlanta, Georgia

1215

Objectives: Previously reported NET imaging agent, (S,S)-[11C]MeNER, displayed a high binding affinity and selectivity towards NET in vivo. However, specific binding to NET did not reach peak equilibrium during a 90 min PET measurement. In order to improve the biokinetics of this imaging agent, we have prepared a new reboxetine derivative, (2S,3S)-2-[{alpha}-(2-methylphenylthio)phenylmethyl]morpholine (SMENET), as a new NET PET imaging agent. This ligand was radiolabeled with C-11 and evaluated in monkeys by microPET and PET.

Methods: (S,S)-SMENET was synthesized stereospecifically. In vitro competition assays were performed in cells expressing human NET, SERT and DAT. Radiolabeling was accomplished by palladium catalyzed coupling of N-t-Boc aryl-stannane precursor with 11CH3I followed by deprotection with CF3COOH. In vivo regional brain uptake and kinetics were determined in anesthetized rhesus monkeys using a Concorde microPET P4 and in awake rhesus monkeys using a high-resolution research tomography.

Results: (S,S)-SMENET exhibited high affinity and selectivity for the NET (Ki = 0.30 nM) over SERT (Ki = 14.80 nM) and DAT (Ki = 275 nM). After HPLC purification, (S,S)-[11C]SMENET was obtained in 27% decay-corrected RCY with a radiochemical purity of >98%, and a log P7.4 of 2.34. (S,S)-[11C]SMENET showed high uptake in NET-rich regions with peak achieved between 22.5-32.5 min. The highest ratios relative to caudate were 1.34, 1.38, and 1.61 for the thalamus, midbrain, and LC occurred at 45, 27, and 22 min, respectively. A significant blocking effect was observed in NET-rich regions with the desipramine pretreatment.

Conclusions: These results suggest that (S,S)-[11C]SMENET could be a potential agent for mapping the human NET by PET.





This Article
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Right arrow Articles by Goodman, M.