PET Whole Body Distribution Studies Using [11C]CUMI

Eighteen million people in the United States are currently suffering from Major Depressive Disorder, which is characterized by episodes of low mood, poor self attitude and poor vitality. Of those suffering from Major Depressive Disorder (MDD), only one third completely improve, but even among these cases, there is a waiting period of several weeks or more during which antidepressants take effect. Our inability to adequately treat MDD is evident in its being ranked number one in Disability Adjusted Life Years (DALY) among persons aged 15-44. Given this profound burden, improving our understanding of the molecular basis of MDD is of utmost importance in the development of novel antidepressant medications.

Serotoninergic neurotransmission is implicated in MDD, as demonstrated by the relative success of selective serotonin reuptake inhibitors (SSRIs). SSRIs block the reuptake of serotonin through the serotonin transporter, which then increases serotonin at the synaptic cleft. Serotonin then binds to 5-HT(1A) receptors, which are G-protein coupled receptors that are present both presynaptically and postsynaptically. Presynaptically, these receptors act as autoinhibitory receptors, triggering decreased firing rates and decreased serotonin release. This autoinhibitory mechanism is believed to be the reason why patients experience a delay in symptomatic improvement after initiation of SSRIs. Serotonin binding to postsynaptic receptors mediates symptomatic improvement of depression. Multiple positron emission tomography (PET) studies on 5-HT(1A) have been published. However, none of these studies use 5-HT(1A) agonists, which are specific for the high affinity, G-protein coupled and active state of the 5-HT(1A) receptor. We would therefore like to establish the use of the 5-HT(1A) radiolabelled agonist, [(11)C]CUMI, here at NIH.

The purpose of this study is to perform whole body PET studies in healthy volunteers in order to estimate radiation absorbed doses for [(11)C]CUMI. Future experiments will include studies on Major Depressive Disorder.

• INCLUSION CRITERIA:

• Subjects must be adults between 18-65 years old.
• Subjects must be able and willing to give written informed consent.

Exclusion criteria

• With the exception of substance abuse disorders, any past or current Axis I diagnosis as assessed by clinical interview which may include the SCID-NP. With regard to substance abuse, we will allow a history of substance abuse so long as criteria for substance dependence are not met, and the episode(s) of substance abuse occurred over 1 year prior to study enrollment.
• Any prior use of Lysergic acid diethylamide (LSD).
• Use of ecstasy more than 3 times in a lifetime.
• Any history of psychotic symptoms.
• If female, any history of Premenstrual Dysphoric Disorder (PMDD), because PMDD has been shown to correlate with changes in 5-HT1A distribution in brain.
• In women, irregular menses such that the subject will not know the phase of the menstrual cycle at time of scanning.
• Clinically significant laboratory abnormalities.
• Psychotropic medication use (including benzodiazepines and illicit drugs) during the 28 days (42 day for fluoxetine) prior to the PET scan.
• Serious medical problems including but not limited to chronic neurological disease such as multiple sclerosis, autoimmune diseases or any cardiopulmonary disease that would increase risks associated with sedation.
• Positive HIV status.
• Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.
• History of fetal alcohol syndrome or other neurodevelopmental disorder.
• Recent exposure to radiation (i.e., PET from other research) which when combined with this study would be above the allowable limits.
• Positive urine drug screen.
• Inability to lie flat on camera bed for about 2.5 hours.
• Pregnancy at time of scan (beta HCG will be measured in all female patients within 24 hours of scan and must be negative).