Evaluation of Specific PET Radioligand Binding To Translocator Protein

Objective:

The 18kDa Translocator Protein (TSPO, formerly known as the peripheral benzodiazepine receptor (PBR)) is expressed in activated microglia and reactive astrocyte. It has therefore been used as an imaging target for positron emission tomography (PET) to investigate diseases involving microglial activation and/or macrophage recruitment, such as multiple sclerosis, herpes encephalitis, Parkinson s disease, Alzheimer s disease and ischemic stroke. The vast majority of PET studies reported to date have used 11C-(R,S) and 11C-(R)-PK 11195, a 3-isoquinolinecarboxamide antagonist, with nanomolar affinity for TSPO. Several second generation radioligands, including 11C-PBR28, 11C-DPA-713, and 11C-ER176 have been developed. Although these ligands have greater signal to noise (specific to nondisplaceable uptake) ratio than 11C-(R)-PK 11195,their binding to TSPO is affected by a single nucleotide polymorphism (SNP). Specific to nondisplaceable ratio of 11C-PBR28 has recently been reported. However, no one has ever measured the specific to nondisplaceable ratio of other TSPO radioligands including 11C-(R)-PK 11195, 11C-DPA-713 and 11C-ER176 in human subjects. In addition, differences in this binding site between species preclude comparisons based on studies in animals. The purposes of this study are to measure the signal to noise ratio (i.e., ratio of specific to non-displaceable uptake) of 11C-(R)-PK 11195, 11C-ER176 and 11C-DPA-713 in human subjects with two scans in each subject: at baseline and after emapunil, an agonist at the TSPO site and a putative anxiolytic based on studies in animals and in humans and study the effect of the SNP on the in vivo specific binding of the PET ligands.

Study population:

75 healthy volunteers in total aged 18 to 55 years. Of these, 25 will have 11C-(R)-PK 11195, 25 have 11C-DPA-713 scans, and 25 have 11C-ER176.

Design: