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This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jnumed.108.060723v1 50/9/1509    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, J. L. Articles by Kung, H. F. PubMed PubMed Citation Articles by Wang, J. L. Articles by Kung, H. F.

In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2'-((Dimethylamino)Methyl)-4'-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

¹ Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ² Department of Radiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence: For correspondence or reprints contact: Hank F. Kung, Department of Radiology, School of Medicine, University of Pennsylvania, 3700 Market St., Suite 305, Philadelphia, PA 19104. E-mail: kunghf{at}gmail.com

PET of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiologic functions as well as disease states involving the serotonergic system. The goal of this study was to further develop and refine a series of 4'-fluoroalkoxy–substituted, ¹⁸F-radiolabeled SERT imaging agents. 2-(2'-((Dimethylamino)methyl)-4'-(4-¹⁸F-fluorobutoxy)phenylthiol)benzenamine (3) and 2-(2'-((dimethylamino)methyl)-4'-(5-¹⁸F-fluoropentoxy)phenylthiol)benzenamine (4) were synthesized and evaluated along with 2 previously reported compounds of this series, 2-(2'-((dimethylamino)methyl)-4'-(2-¹⁸F-fluoroethoxy)phenylthiol)benzenamine (1) and 2-(2'-((dimethylamino)methyl)-4'-(3-¹⁸F-fluoropropoxy)phenylthiol)benzenamine (2). Methods: The in vitro binding affinities of compounds 3 and 4 were determined in monoamine transporter–transfected LLC-PK₁ cell homogenates. In vivo localization of the respective ¹⁸F-labeled compounds was evaluated by biodistribution studies in male Sprague–Dawley rats. Compound 3 was selected for further examination by autoradiographic and PET studies in rats. Results: The corresponding mesylate precursors of 3 and 4 were radiolabeled with ¹⁸F within 75–90 min. Radiochemical yield was 6%–35%, specific activity was 15–170 GBq/µmol, and radiochemical purity was greater than 97% (end of synthesis). The compounds showed subnanomolar binding affinities for SERT (inhibition constants, 0.51 and 0.76 nM, respectively), had brain uptake at 2 min of 1.25 and 0.68 percentage injected dose per gram, respectively, and possessed high target-to-nontarget (hypothalamus-to-cerebellum) ratios at 120 min after injection (6.51 and 5.70, respectively). Autoradiographic studies of ¹⁸F-3 showed selective localization in SERT-rich brain regions. PET studies of ¹⁸F-3 showed clear localization in the midbrain, thalamus, and striatum. Conclusion: This compound series was found to have potential for producing a suitable ¹⁸F-radiolabeled PET radiotracer for SERT. Compound 4, the pentoxy derivative, had the lowest brain uptake and target-to-nontarget ratio. Compound 3, the butoxy derivative, had a lower target-to-nontarget ratio than compounds 1 (ethoxy derivative) and 2 (propoxy derivative). Compounds 1 and 2 both hold promise as SERT radioimaging agents, but because of cost limitations, only compound 2 will be evaluated in further studies.

Key Words: brain imaging • radioligand • SERT • 5-HTT • ¹⁸F

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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JNM 2009 50: 11A-12A. [Full Text]