The objectives of this study are to document the pharmacokinetics of the adequacy of DAT
receptor occupancy d-MPH formulation in three doses (20 mg, 30 mg, and 40 mg) using PET
scanning with C-11 Altropane as the ligand across a range of times. It has been estimated
that MPH is effective when the average CNS DAT occupancy is 50% or greater. Focalin XR has
been shown to be clinically effective in an analog classroom as early as 1 hour and as late
as 12 hours. Therefore, it is hypothesized that the average DAT occupancy will be adequate
(50% or greater) at time periods corresponding to the times of clinical efficacy.
The first objective is to examine the onset of action by testing whether average DAT
occupancy will be adequate (50% or greater) at 1 hour after dosing for each dose tested (20
mg, 30 mg, 40 mg).
The second objective is to test the adequacy of average DAT occupancy in a range of later
times for each dose. The times chosen (8, 10 and 12 hours) correspond to times Focalin XR
has been shown to be clinically effective in an analogue classroom study. A range of times
have been chosen since, while effective at 12 hours, the degree of clinical effectiveness
decreased with later time periods. The adequacy of DAT occupancy across this range of time
periods will provide important details on the in vivo molecular action of the medicine at
periods of critical clinical activity.
The third exploratory objective is to examine a time period later then those previously
tested with the highest dose. Since the clinical effectiveness of Focalin XR has not been
tested out to 14 hours, it is unknown whether it is effective at 14 hours. If Focalin XR
were to be effective at 14 hours it would be more likely at the highest dose.
Stimulants have been shown to be very effective in the treatment of Attention Deficit
Hyperactivity Disorder (ADHD).  Studies have shown that full day treatment is often
preferable to shorter treatment  and recent guidelines advise full day treatment. 
However, there are many barriers to giving multiple doses of short acting medicine. New
delivery systems have evolved to overcome tachyphylaxis and provide effective long-acting
treatment with a single pill.  One of the new formulations is the spheroidal oral drug
absorption system (SODAS). SODAS consists of capsules with two types of beads in a 1 to 1
ratio. One type of bead provides immediate release methylphenidate (IR MPH), and the other
type of bead consists of MPH coated with a polymer that delays release for 4 hours. SODAS
MPH has been shown to be effective in clinical studies . However, the mechanism of
action remains unclear. While pharmacokinetic studies have shown a double pulse profile in
the serum , the central nervous system pharmacokinetics are unknown. Understanding the
central nervous system pharmacokinetic properties is critical for new drug development for
ADHD, especially for drugs of different lengths of action.
The d-MPH form has been shown to be the active enantiomer of MPH. Studies have shown that
the duration of action of d-MPH is longer than that of racemic MPH. Clinical studies of
once a day d-MPH has demonstrated efficacy in children, adolescents and adults with ADHD.
Understanding the central nervous system pharmacokinetic properties of the SODAS formulation
of the longer-acting (d) enantiomer will provide critical knowledge of its mechanism of
The main target of MPH in the brain is the dopamine transporter (DAT) . There is now an
exquisitely sensitive methodology to measure DAT occupancy using C-11 Altropane and Positron
Emission Tomography (PET) . The time course of decay of the C-11 Altropane permits
repeated imaging, thus allowing documentation of the pharmacokinetics of DAT receptor
occupancy. A group at Massachusetts General Hospital has previously documented the central
nervous system pharmacokinetics of several psychiatric drugs using similar techniques
To this end, this protocol seeks to document the pharmacokinetics of DAT receptor occupancy
of d-MPH using PET and C-11 Altropane. It has been estimated that MPH is effective when the
CNS DAT occupancy is 50% or greater. This aim of this study will be to measure CNS DAT
occupancies at extended time points after administration of d-MPH. This research will
provide novel and unique information toward a better understanding of the mechanism of
action of long-acting stimulant formulations to enable new drug development.
1. Signed written informed consent to participate in the study.
2. Age: 18 -45, inclusive
3. If female, non-pregnant, non-nursing with a negative serum pregnancy test.
4. Female subjects will agree to use an acceptable and effective form of birth control
during the course of their study participation.
5. Supine and standing blood pressure < 150/90 mmHg.
6. Heart rate, after resting for 5 minutes, within the range 46-90 beats/min.
7. Right handed.
1. Diagnosis of any psychotic disorder, bipolar disorder, severe depression, severe
anxiety, or Autism. Subjects with mild mood, oppositional, conduct, and anxiety
disorders may be permitted to participate if considered appropriate by the
2. Scores of Baseline Scales:
- Hamilton Depression Scale > 12 (out of a possible 67 on the 21-item scale)
- Beck Depression Inventory > 19 (out of a possible 63 on the 21-item scale)
- Hamilton Anxiety Scale > 21 (out of a possible 56 on the 14-item scale) 
3. Subjects with motor tics or with a family history or diagnosis of Tourette's
4. History of head trauma with loss of consciousness, organic brain disorders, seizures,
or neurosurgical intervention.
5. Any clinically significant chronic medical condition, in the judgment of the
6. In the judgment of the investigator, has a mental impairment as evidenced by an I.Q.
7. Exposure to dopamine receptor antagonists within the previous three (3) months.
8. Exposure to radiopharmaceuticals within four (4) weeks prior to PET scan.
9. Subjects receiving psychotropic medication including MAO inhibitors within the past 6
to 12 months.
10. Any clinically significant abnormality in the screening laboratory tests, vital
signs, or 12 lead ECG, outside of normal limits.
11. Any pre-existing structural cardiac abnormalities.
12. A history or known family history of long QT syndrome or QTc >450 ms (males) or >470
13. Any family history of cardiac sudden death.
14. QTc prolongation of QTc > 450 ms (male) or 470 ms (female), hypertension or cardiac
arrhythmia, or increased heart rate for age in the judgment of the investigator at
15. A history of cardiac structural abnormality
16. Any woman of childbearing potential who is seeking to become pregnant or suspects
that she may be pregnant.
17. Subjects with a known recent history (within the past six (6) months) of illicit drug
or alcohol dependence.
18. Subjects diagnosed with glaucoma.
19. Subjects at risk for MPH toxicity (e.g. individuals with arrhythmias, coronary artery