Brain Kinetics of Methylphenidate (Ritalin) Enantiomers After Oral Administration YU-SHIN DING, * S. JOHN GATLEY, PANAYOTIS K. THANOS, COLLEEN SHEA, VICTOR GARZA, YOUWEN XU, PAULINE CARTER, PAYTON KING, DON WARNER, NICHOLAS B. TAINTOR, DANIEL J. PARK, BEA PYATT, JOANNA S. FOWLER, AND NORA D. VOLKOW Chemistry and Medical Departments, Brookhaven National Laboratory, Upton, New York 11973-5000 KEY WORDS methylphenidate; Ritalin; ADHD; dopamine transporter; positron emission tomography; chiral drugs ABSTRACT Methylphenidate (MP) (Ritalin) is widely used for the treatment of atten- tion deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d- and l-threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in the d-isomer. A recent report that intraperitoneally (i.p.) administered l-threo-MP displayed potent, dose-dependent inhibition of cocaine- or apomorphine-induced locomotion in rats, raises the question of whether l-threo-MP has a similar effect when given orally. It has been speculated that l-threo-MP is poorly absorbed in humans when it is given orally because of rapid presystemic metabolism. To investigate whether l-threo-MP or its metabolites can be delivered to the brain when it is given orally, and whether l-threo-MP is pharmacologically active. PET and MicroPET studies were carried out in baboons and rats using orally delivered C-11-labeled d- and l-threo-MP ([methyl- 11 C]d-threo-MP and [methyl- 11 C]l-threo-MP). In addition, we assessed the effects of i.p. l-threo-MP on spontaneous and cocaine-stimulated locomotor activity in mice. There was a higher global uptake of carbon-11 in both baboon and rat brain for oral [ 11 C]l-threo-MP than for oral [ 11 C]d-threo-MP. Analysis of the chemical form of radioactivity in rat brain after [ 11 C]d-threo-MP indicated mainly unchanged tracer, whereas with [ 11 C]l-threo-MP, it was mainly a labeled metabolite. The possibility that this labeled metabolite might be [ 11 C]methanol or [ 11 C]CO 2 , derived from demethylation, was excluded by ex vivo studies in rats. When l-threo-MP was given i.p. to mice at a dose of 3 mg/kg, it neither stimulated locomotor activity nor inhibited the increased locomotor activity due to cocaine administration. These results suggest that, in animal models, l-threo-MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and enters the brain after oral administration, but that l-threo-MP may not be pharmacologi- cally active. These results are pertinent to the question of whether l-threo-MP contributes to the behavioral and side effect profile of MP during treatment of ADHD. Synapse 53: 168 –175, 2004. © 2004 Wiley-Liss, Inc. INTRODUCTION Racemic methylphenidate (MP, dl-threo-methyl-2- phenyl-2-(2-piperidyl)acetate, Ritalin) is a CNS stimu- lant that is the most commonly prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD). ADHD has become America’s No. 1 childhood psychiatric disorder (Barkley, 1977) with an estimated prevalence of 5–10% of the general population (Swan- son et al., 1998). The therapeutic effect of MP has been linked to its blockade of the dopamine transporter, resulting in enhanced levels of synaptic dopamine (Volkow et al., 2001). We have labeled both d- and l-threo-MP with carbon-11 ([ 11 C]d-threo-MP and [ 11 C]l- threo-MP) and used positron emission tomography (PET) (1994a,b, 1995, 1997) to show high specific bind- Contract grant sponsor: U.S. Department of Energy and Office of Biological Environmental Research; Contract grant number: DE-AC02-98CH10886; Con- tract grant sponsor: National Institutes of Health, National Institute for Bio- medical Imaging and Bioengineering; Contract grant number: EB002630; Con- tract grant sponsor: National Institute on Drug Abuse; Contract grant number: DA-06278; Contract grant sponsor: Office of National Drug Control Policy. *Correspondence to: Yu-Shin Ding, Ph.D., Neuroscience and Imaging Group, Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973-5000. E-mail: ding@bnl.gov Received 14 October 2003; Accepted 26 April 2004 DOI 10.1002/syn.20046 Published online in Wiley InterScience (www.interscience.wiley. com). SYNAPSE 53:168 –175 (2004) © 2004 WILEY-LISS, INC.