Journal Article

Measurement of B sub(max) and K sub(d) with the glycine transporter 1 radiotracer super(18)F-MK6577 using a novel multi-infusion paradigm

Holden, Daniel, Zheng, Ming-Qiang, Huang, Yiyun, Xia, Yan, Ropchan, Jim, Kapinos, Michael, Carson, Richard E, Lin, Shu-fei, Gallezot, Jean-Dominique

2015

Overview

Glycine is a co-agonist of glutamate at the NMDA receptor. Glycine transporter 1 (GlyT1) inhibitors are reported to be potential therapeutic agents for schizophrenia. super(18)F-MK6577 is a new positron emission tomography (PET) radiotracer useful for imaging brain GlyT1 and its occupancy in humans. We devised a novel multi-infusion paradigm of radiolabeled and unlabeled compound and an iterative linear/nonlinear alternating fitting method to allow for the determination of in vivo affinity (K sub(d)) and target concentration (B sub(max)) images, constraining K sub(d) to be uniform across the brain. This paradigm was tested with super(18)F-MK6577 in baboons. Voxel-based analysis produced high quality B sub(max) images and reliable K sub(d) estimates, and also suggested that the nondisplaceable distribution volume (V sub(ND)) is not uniform throughout the brain. In vivo GlyT1 K sub(d) was estimated to be 1.87 nmol/L for super(18)F-MK6577, and the rank order of GlyT1 distribution measured in the baboon brain was: high in the brainstem (133 nmol/L), medium in the cerebellum (83 nmol/L), and low in the cortex (30 nmol/L). These in vivo K sub(d) and B sub(max) values agreed well with those determined in vitro, thus validating our novel multi-infusion approach.

• Subject: Papio