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Quantitative Positron Emission Tomography Studies of the Serotonin Transporter in Humans Previously Treated with the Appetite Suppressants Fenfluramine or Dexfenfluramine

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Abstract

Purpose

The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [11C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters.

Procedures

Subjects previously treated with fenfluramines for weight loss (N = 15) and age-matched controls (N = 17) underwent PET studies with [11C] McN5652. Global and regional distribution volumes (DVs) of [11C] McN5652 were compared in the two subject groups using parametric statistical analyses.

Results

Compared to controls, subjects previously exposed to fenfluramines had significant reductions in [11C]McN5652 binding in 14 of 15 regions of interest, more than four years after drug discontinuation.

Conclusions

These results are the first to provide direct evidence for fenfluramine-induced 5-HT neurotoxicity in humans.

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Acknowledgments

This manuscript was supported by PHS Grants DA00206 (Ricaurte); AA11653 (Szabo), NSF Grant No. 843 (Szabo), and NCRR grant M01RR002719 (Klag). We thank Paul Nuzzo for his assistance with statistical analyses, and Audra de Ridder for her assistance with recruiting subjects. We appreciate the important contributions of Jozsef Varga, Ph.D. whose work was pivotal for the development of the image analysis package PMT that was used in this project.

We appreciate the following contributions to PET imaging and image analysis: David Clough, CNMT and Karen Edmonds, CNMT for performance of PET studies; John Hilton for HPLC analysis of tracer metabolites. None of the authors has a financial or other conflict of interest that might potentially bias this work.

Role of Authors. Drs. McCann and Ricaurte designed the study and supervised all aspects of the research related to fenfluramine subjects, except for PET scanning procedures. Dr. Szabo supervised all of the PET studies described. Drs. Vranesic and Seckin assisted in PET data analysis. Dr. Wand was responsible for the recruitment and assessment of control subjects. Ms. Duval assisted with the data analysis and figure preparation for the manuscript. Dr. Dannals supervised synthesis of the radiotracer utilized. Drs. McCann, Ricaurte, and Szabo took the lead in writing the manuscript. All authors reviewed the manuscript and suggested changes when deemed appropriate.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD, 21224, USA

    Una D. McCann, Gary Wand & Anna DuVal

  2. Department of Radiology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Zsolt Szabo, Melin Vranesic, Esen Seckin & Robert F. Dannals

  3. Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Gary Wand

  4. Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    George A. Ricaurte

Authors
  1. Una D. McCann
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  2. Zsolt Szabo
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  4. Esen Seckin
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  5. Gary Wand
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  6. Anna DuVal
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  7. Robert F. Dannals
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  8. George A. Ricaurte
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Corresponding author

Correspondence to Una D. McCann.

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McCann, U.D., Szabo, Z., Vranesic, M. et al. Quantitative Positron Emission Tomography Studies of the Serotonin Transporter in Humans Previously Treated with the Appetite Suppressants Fenfluramine or Dexfenfluramine. Mol Imaging Biol 9, 151–157 (2007). https://doi.org/10.1007/s11307-007-0082-7

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