Naltrexone occupancy at kappa opioid receptors investigated in alcoholics by PET occupancy at kappa opioid receptors investigated in alcoholics by PET

Objectives: Earlier work from our group at Yale using a human alcohol drinking paradigm (ADP) suggested that family history (FH) of alcoholism and gender may mediate responses to Naltrexone (NTX) (1). NTX binds with varying degrees to Mu, Delta and Kappa opioid receptors and a further understanding of the association of clinical outcomes with receptor occupancy at each binding site could advance medication targeting for drinking behaviors. Weerts and colleagues (2) have shown negligible variability in percent occupancy of Mu receptors by NTX (95 +/- 5%) but high variability in occupany at Delta receptors (21 +/- 14%) in alcoholics using PET imaging. This suggests that action of NTX at Delta sites could explain variable outcomes of NTX treatment. The Kappa binding site was not interrogated at the time because there was no kappa tracer available. We have developed a selective Kappa PET tracer, ¹¹C-LY2975050 (3). Our objective was to use PET imaging with ¹¹C-LY2975050 to determine the level and the variability in NTX occupancy of Kappa receptors in alcoholics and to determine if occupancy and variability differs by sex and/or by FH of alcoholism.

Methods: Male and female alcoholics participated in the ADP as well as a baseline PET scan with ¹¹C-LY2975050. Following 7 days of treatment with NTX (25mg, 50mg, 100mg remainder of week) they returned for a second ADP and a second PET scan.

Results: The mean NTX whole-brain occupancy at Kappa was 87.2 +/- 19.0% (n=33). There were no differences in mean occupancy between males (n=25) and females (n=8) 87.4 +/- 18.8% vs 86.4 +/- 22.1%, respectively. There were no differences in mean occupancy by family history (FHP: 88.1 +/- 16.2% (n=17) vs FHN: 86.2 +/- 22.6% (n=16)).

Conclusion: Our preliminary observations did not reveal differences in NTX binding to Kappa by sex or family history. It is interesting to note that we observed even greater variability in NTX binding to Kappa receptors than was observed at Delta, previously (2). Possible relationships between NTX binding at Kappa and changes in drinking behavior in the ADP sessions are being investigated. Research Support: NIH grant R01AA021818, JRP supported by NSF GRFP grant DGE-1122492 References: (1) Krishnan-Sarin S, Biological Psychiatry, 2007. (2) Weerts E, Neuropsychopharmacology, 2008. (3) Kim SJ, J Nuclear Medicine, 2013.