Ž . Brain Research 834 1999 1–5 www.elsevier.comrlocaterbres Research report Measurement of human brain dexfenfluramine concentration by 19F magnetic resonance spectroscopy James D. Christensen a,b,c,d , Deborah A. Yurgelun-Todd a,b , Suzann M. Babb a,b , Staci A. Gruber a,b , Bruce M. Cohen a,b , Perry F. Renshaw a,b, ) a Brain Imaging Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA b Consolidated Department of Psychiatry, HarÕard Medical School, Boston, MA, USA c ( ) VA Medical Center 151 , 4500 South Lancaster Road, Dallas, TX 75216, USA d UniÕersity of Texas Southwestern Medical School, TX 75216, USA Accepted 30 March 1999 Abstract Ž . Objective: The goals of this study were to quantitate the brain concentration of the anorectic drug dexfenfluramine DF in human subjects receiving clinical doses of DF and to determine whether human brain DF concentrations approach those reported to cause irreversible neurochemical changes in animals. Each subject’s brain DF concentration was measured several times over an extended period of DF treatment to determine whether drug accumulation in the brain would plateau or continue to increase throughout the Ž . treatment period. Design: Fluorine magnetic resonance spectroscopy 19F-MRS was used to directly detect and quantitate brain levels of Ž . the fluorinated drug dexfenfluramine and its active metabolite dex-norfenfluramine dNF . Patients received 15 mg dexfenfluramine BID for 90 days. 19F-MRS measurements were performed at baseline and at three times during the treatment period. Participants: Twelve Ž . women age 38–54 years who were obese, with body mass indices of 28.4–37.4, but otherwise healthy. Results: The combined concentration of DF and nDF reached steady-state in the human brain after approximately 10 days of treatment. The steady-state brain concentration averaged approximately 4 mM and did not tend to increase significantly during the 90 day treatment period. Conclusions: These results demonstrate that fluorinated drugs can be quantified using 19F MRS at concentrations below 10 mM in the human brain. The time-course data suggest that brain DF concentrations parallel DF plasma pharmacokinetics in humans. Measured brain dexfenflu- raminernor-dexfenfluramine concentrations were well below levels previously found to cause irreversible brain alterations in animals. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Dexfenfluramine; Fluorine; Magnetic resonance spectroscopy; Neurotoxicity; Obesity; Pharmacokinetics 1. Introduction Obesity is a major health problem in the United States affecting millions of people and costing billions of dollars for medical care and in lost productivity. Certain seroton- ergic drugs act as appetite suppressants by enhancing feelings of satiation while eating and reducing hunger w x between meals 23,3,4,25 , making them effective agents w x in a program of treatment for obesity 8,12,18 . Ž . Fenfluramine FEN , which alters neuronal serotonin Ž . 5-hydroxytryptamine, 5-HT release and reuptake, has been used clinically as an appetite suppressant in the US ) Corresponding author. Brain Imaging Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA. E-mail: perry@genesis.mclean.org for 20 years. The dextrorotary enantiomer of FEN, dexfen- Ž . fluramine DF , unlike the racemate, is more specific in affecting neuronal serotonin uptake and release while hav- w x ing few other neurochemical effects 18,1,24 . This speci- ficity allows DF to produce its appetite suppressant effects while limiting side effects, such as diarrhea and sedation, which are more commonly seen with the racemate w x 11,13,9 . DF has been used for the treatment of obesity in Europe for 10 years at a dosage level of approximately 0.3 y1 y1 wx mg kg day 5 and was approved by the US Food and Drug Administration in 1996 for weight loss and mainte- nance. Clinical trials have demonstrated that DF treatment is more effective than dieting alone for weight reduction, and initial safety data from these trials and epidemiological data from approximately 10 million patients suggested that w x DF was reasonably well tolerated 8,12,11,5,10 . However, following unexpected reports of possible cardiac valve 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 01441-9