Investigation of three PET ligands as oxytocin receptor biomarkers in marmoset models

Objectives The oxytocin (OT) system has been implicated in various human social behavior disorders. Our research has focused on developing PET ligands for imaging neural OT receptors (OTR) to potentially enable correlations between behavior disorders and OTR density. Our research which has recently proven the lack of OTR in the forebrain of the rhesus monkey led us to conduct preliminary studies using three of our target ligands in marmosets due to their well documented and confirmed OTR density. Our objective was to evaluate these candidates in a marmoset model to provide insight to their utility and for future biomarker development.

Methods Biomarkers 1-3 were generated through previously reported synthetic pathways. Approximately 1.5 mCi of F-18 derivatives (1 and 2) and 3 mCi of the C-11 derivative were injected into an anesthetized marmoset and scanned for 1.5 hours.

Results While 1 appeared to lack the ability to penetrate the brain, significant brain penetration was observed with 2 and modest brain penetration was observed with 3. Of 1-3, specific uptake in the anticipated region of the nucleus accumbens and diagonal band was not observed.

Conclusions The potency for 1-3 are known for the human OTR ( Ki = 7, 17, and 5 nm respectively), but may vary significantly for the marmoset species. An affinity assessment of 1-3 for the marmoset OTR will determine if potency variation caused the lack of specific uptake in the marmoset. The marmoset OTR density is primarily located in the nucleus accumbens and diagonal band. Despite the small size of the animal model and limited OTR density, a faint signal was anticipated in the forebrain, but not detected. Although these compounds are not viable biomarkers for the marmoset, if the potency of 2 is similar to the human OTR, it could be used in behavioral studies due to its antagonistic effect and ability to penetrate the brain. Furthermore, the structural similarity and contrasting results of 1 and 2 may aid in the development of an improved structure for our purpose.

Research Support NIMH grant 5 R21 MH090776