Concurrent PET D2/D3 Receptor Imaging and fMRI Smoking Cue Reactivity in Smokers

NCT01784016 | Withdrawn Phase 1

• 2 other identifiers: SmokingPETD2-3fMRIR21DA031925-01A1
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 3

Brief Summary

This trial aims to determine whether dopamine D3 receptors are elevated in smokers versus nonsmokers and whether correlations exist between D3 receptor binding potential (BP) and functional MRI (fMRI) reactivity to smoking cues, which has been associated with smoking relapse vulnerability. Neuroimaging measures of D3 BP and smoking cue fMRI reactivity will be collected concurrently in otherwise healthy nicotine-dependent smokers and age-matched nonsmokers using a 3 Tesla MRI scanner configured to conduct fMRI and Positron Emission Tomography (PET). We will measure D3 receptor BP using radiolabeled \[11C\]-(+)-PHNO, which has a relatively higher affinity for D3 versus D2 receptors. We hypothesize that D3 BP will be elevated in smokers versus nonsmokers and that in smokers, there will be a positive correlation between smoking cue fMRI reactivity and D3 BP.

Conditions

Nicotine Dependence; Smoking Cue Reactivity; Relapse to Smoking

Outcome Measures

Primary Outcomes (1)

• Dopamine D3 Receptor Binding Potential Difference Between Smokers and Nonsmokers

  We will determine whether dopamine D3 receptor binding potential, a dimensionless number which represents the relative concentration of dopamine D3 receptors available for binding, is elevated in smokers versus nonsmoking controls.

  March 2014

Secondary Outcomes (1)

• Smoking Cue fMRI Reactivity Association with Dopamine D3 Receptor Binding Potential

  March 2014

Study Arms (2)

Healthy Smokers

EXPERIMENTAL

Healthy smokers aged 18-50 years reporting average cigarette consumption of 15 or more cigarettes/day for the past year, providing an expired breath carbon monoxide reading exceeding 10 ppm at screening.

Radiation: [11C]-PHNO

Healthy Nonsmokers

EXPERIMENTAL

Healthy nonsmoking controls aged 18-50 reporting consumption of \<100 cigarettes in their lifetime, none in the last 6 months, providing an exhaled breath carbon monoxide reading of \< 9 ppm at screening.

Radiation: [11C]-PHNO

Interventions

[11C]-PHNO RADIATION

\[11C\]-PHNO will be administered once intravenously to conduct Positron Emission Tomography (PET) measurements of dopamine D2/D3 binding potential.

Also known as: 11C-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol

Healthy Nonsmokers; Healthy Smokers

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• competent to provide written informed consent
• Smokers: self-report of smoking 15 or more cigarettes/day for the past year, self-report of smoking first cigarette of the day within 30 minutes of awakening, meets DSM-IV criteria for Nicotine Dependence, provides expired breath carbon monoxide reading of \> 10 ppm at enrollment
• Nonsmokers: self-report of consuming \<100 cigarettes in their lifetime, none in the last 6 months, provides expired breath carbon monoxide reading of \< 9 ppm at enrollment
• Women of childbearing potential: negative STAT serum beta-human chorionic gonadotrophin pregnancy test before scanning

You may not qualify if:

• pregnant or able to become pregnant and not willing to undergo blood pregnancy test
• unstable medical illness with likely hospitalization for treatment within 6 months
• life-threatening arrhythmia, cerebro-vascular or cardiovascular event within 6 months of enrollment; liver function tests elevated over 2.5x normal; CNS tumor or seizure disorder
• users of other tobacco- or nicotine-containing products (gum, patches, e-cigarettes)
• lifetime history of DSM-IV bulimia, organic mental disorder, brain injury or psychotic disorder
• month history of non-nicotine substance use disorder or major depression
• history of multiple adverse drug reactions
• current use of excluded concomitant medications (smoking cessation medications)
• known history of allergic reaction to the PET ligand \[11C\]-PHNO, its components, or any medication

Sponsors & Collaborators

• Mclean Hospital: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (3)

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging

Charlestown, Massachusetts, 02129, United States

Location

Related Publications (6)

• Janes AC, Pizzagalli DA, Richardt S, deB Frederick B, Chuzi S, Pachas G, Culhane MA, Holmes AJ, Fava M, Evins AE, Kaufman MJ. Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. Biol Psychiatry. 2010 Apr 15;67(8):722-9. doi: 10.1016/j.biopsych.2009.12.034. Epub 2010 Feb 20.

  PMID: 20172508 BACKGROUND

• Le Foll B, Diaz J, Sokoloff P. Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats. Synapse. 2003 Mar;47(3):176-83. doi: 10.1002/syn.10170.

  PMID: 12494400 BACKGROUND

• Searle G, Beaver JD, Comley RA, Bani M, Tziortzi A, Slifstein M, Mugnaini M, Griffante C, Wilson AA, Merlo-Pich E, Houle S, Gunn R, Rabiner EA, Laruelle M. Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol Psychiatry. 2010 Aug 15;68(4):392-9. doi: 10.1016/j.biopsych.2010.04.038.

  PMID: 20599188 BACKGROUND

• Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, Jenkinson M, Laruelle M, Rabiner EA, Gunn RN. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage. 2011 Jan 1;54(1):264-77. doi: 10.1016/j.neuroimage.2010.06.044. Epub 2010 Jun 30.

  PMID: 20600980 BACKGROUND

• Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, Houle S, Seeman P, Ginovart N. Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. J Med Chem. 2005 Jun 16;48(12):4153-60. doi: 10.1021/jm050155n.

  PMID: 15943487 BACKGROUND

• Pak AC, Ashby CR Jr, Heidbreder CA, Pilla M, Gilbert J, Xi ZX, Gardner EL. The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions. Int J Neuropsychopharmacol. 2006 Oct;9(5):585-602. doi: 10.1017/S1461145706006560. Epub 2006 Aug 31.

  PMID: 16942635 BACKGROUND

MeSH Terms

Conditions

Tobacco Use Disorder

Interventions

naxagolide

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Study Officials

• Marc J. Kaufman, Ph.D.

  Mclean Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Translational Imaging Laboratory, McLean Hospital

Study Record Dates

• First Submitted: January 30, 2013
• First Posted: February 5, 2013
• Study Start: January 1, 2014
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: May 23, 2014

Record last verified: 2014-05

Locations

US (3)