PET Study Examining the Dopaminergic Activity of Armodafinil in Adults
PET Study Examining the Dopaminergic Activity of Armodafinil in Adults
The specific aims of this study are 1) to document the Dopamine Transporter (DAT) receptor
 occupancy of armodafinil using positron emission tomography (PET) scanning with C-11
 altropane as the ligand and 2) to document the increased intrasynaptic dopamine produced by
 armodafinil using PET scanning with C-11 raclopride as the ligand. We hypothesize that DAT
 occupancy will be low with armodafinil; less than the DAT occupancy produced by therapeutic
 doses of methylphenidate. We also hypothesize that increases in intrasynaptic dopamine will
 be relatively low with armodafinil.
Modafinil produces a unique spectrum of pharmacological effects including enhanced vigilance,
 arousal, and wakefulness in human subjects (Bastuji and Jouvet 1988). The drug is widely used
 to treat narcolepsy (Banerjee, Vitiello et al. 2004), but is also effective in Attention
 Deficit Hyperactivity Disorder (ADHD) (Biederman, Swanson et al. 2005). Notwithstanding the
 expanding clinical indications for modafinil, the neurochemical mechanisms that produce
 therapeutic improvement remain unresolved. Pre-clinically, modafinil is a weak inhibitor of
 the DAT, and displays no affinity for dopamine receptor subtypes (Mignot, Nishino et al.
 1994). Further evidence supporting low dopaminergic activity is the low abuse potential of
 modafinil (Jasinski 2000). Various theories have been proposed as alternative modes of action
 including enhancement of glutamate release and inhibition of Gamma-aminobutyric acid (GABA)
 release in various brain regions (Ferraro, Antonelli et al. 1997; Ferraro, Antonelli et al.
 1997; Ferraro, Antonelli et al. 1999). However, the exact mechanisms of action of modafinil
 and the principle active metabolite, armodafinil, are unknown. Understanding these mechanisms
 of action is important in assessing the potential therapeutic role of armodafinil. We will
 test to see if there are differences in the degree of DAT occupancy and D2 binding of
 armodafinil compared with that of traditional stimulants.

 The main target of typical stimulants in the brain is the dopamine transporter (DAT) (Volkow,
 Wang et al. 1998). We have an exquisitely sensitive methodology to measure DAT occupancy
 using C-11 altropane and Positron Emission Tomography (PET) (Fischman, Bonab et al. 2001).
 Our group has previously documented the central nervous system pharmacokinetics of several
 psychiatric drugs (including methylphenidate) using similar techniques. (Christian, Livni et
 al. 1996; Fischman, Bonab et al. 1996; Fischman, Alpert et al. 1997; Salazar and Fischman
 1999; Fischman, Alpert et al. 2002; Spencer, Biederman et al. 2006).

 Increases in intrasynaptic (extracellular) dopamine concentrations associated with
 medications are routinely measured by changes in C-11 raclopride binding in PET scans. C-11
 raclopride binds to postsynaptic D-2 receptors. If the intrasynaptic concentration of
 dopamine increases, it competes with raclopride leading to a weaker signal (i.e. decreased
 raclopride binding to D-2 receptors). After administration of a stimulant, associated
 increases in intrasynaptic dopamine compete with C-11 raclopride binding in this manner
 (Volkow, Wang et al. 2002). By using this technology we can document the change in D-2
 binding in the intrasynaptic space achieved by armodafinil, and compare it to that achieved
 by a typical stimulant.

 To this end, using two PET ligands (C-11 altropane and C-11 raclopride), this protocol seeks
 to compare the DAT receptor occupancy and the increased intrasynaptic dopamine produced by
 armodafinil to previous studies of methylphenidate. This research will provide novel and
 unique information toward better understanding the mechanisms of action of armodafinil in
 comparison to those of typical stimulants.
Inclusion Criteria:

 1. Signed written informed consent to participate in the study.

 2. Age: 18 - 35

 3. If female, non-pregnant, non-nursing with a negative serum pregnancy test and using an
 adequate form of birth control.

 4. Supine and standing blood pressure within the range 110/60 to 150/95 mmHg.

 5. Heart rate, after resting for 5 minutes, within the range 46-90 beats/min.

 6. Right-handed.

 Exclusion Criteria:

 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 investigator.

 2. Scores of Baseline Scales:

 Hamilton Depression Scale > 17 (out of a possible 67 on the 21-item scale)(Hamilton
 1960) Beck Depression Inventory > 19 (out of a possible 63 on the 21-item scale)(Beck,
 Ward et al. 1961) Hamilton Anxiety Scale > 21 (out of a possible 56 on the 14-item
 scale) (Hamilton 1959)

 3. Tics or Tourette's Syndrome.

 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
 investigator.

 6. Mental impairment as evidenced by an I.Q. <75.

 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.

 10. Any clinically significant abnormality in the screening laboratory tests, vital signs,
 or 11-lead ECG, outside of normal limits.

 11. Any woman of childbearing potential who is seeking to become pregnant or suspects that
 she may be pregnant.

 12. Subjects with a known recent history (within the past six (6) months) of illicit drug
 or alcohol dependence.