Measurement of B_max and K_d with the Glycine Transporter 1 Radiotracer ¹⁸F-MK6577 using a Novel Multi-Infusion Paradigm

Abstract

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.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 d ) and target concentration (B max ) images, constraining K d to be uniform across the brain. This paradigm was tested with 18 F-MK6577 in baboons. Voxel-based analysis produced high quality B max images and reliable K d estimates, and also suggested that the nondisplaceable distribution volume (V ND ) is not uniform throughout the brain. In vivo GlyT1 K d was estimated to be 1.87 nmol/L for 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 d and B max values agreed well with those determined in vitro, thus validating our novel multi-infusion approach.

Comparative evaluation of two glycine transporter 1 radiotracers [11C]GSK931145 and [18F]MK-6577 in baboons

“…This conclusion is in agreement with results shown in Table : higher regional BP ND values were found for [ 18 F]MK‐6577, as calculated using regional V T values from the baseline scans and V ND derived from the blocking studies in the same baboon. Given the slope of 0.321 for the regression line in Figure , plasma free fraction of 16% for [ 18 F]MK‐6577 and 5.3% for [ 11 C]GSK931145 from this study, and K d = 1.87 nM for [ 18 F]MK‐6577 as reported recently (Xia et al, ), the in vivo K d of [ 11 C]GSK931145 as derived as 1.93 nM. In another word, using this linear regression analysis, we could deduce similar binding affinities of [ 18 F]MK‐6577 than [ 11 C]GSK931145 for GlyT1 in the baboon brain.…”

“…To compare the specific binding of [ 11 C]GSK931145 and [ 18 F]MK‐6577, linear regression analysis was performed using V T estimates from 12 different brain regions according to the method of Guo et al (). In addition, with the values of plasma free fraction ( f p ) measured for the two tracers in this study and the measured in vivo affinity ( K d ) of 1.87 nM as recently reported for [ 18 F]MK‐6577 (Xia et al, ), the in vivo K d of [ 11 C]GSK931145 was also determined from the slope of the regression line (slope = f P [11C]GSK931145 * K d [18F]MK‐6577 / f P [18F]MK‐6577 / K d [11C]GSK931145 ) (Guo et al, ).…”

The Antimicrobial Peptide 1018-K6 Interacts Distinctly with Eukaryotic and Bacterial Membranes, the Basis of Its Specificity and Bactericidal Activity

“…The values of binding potential (BP = B max / K d ) were also calculated as described elsewhere [ 85 , 86 ].…”

PET Neurochemical Imaging Modes

“…For example, a novel multi-infusion method was recently developed at Yale University, which allows for assessment of B max and K d in vivo (Xia et al, 2015). Continued development in this area will lead to a greater ability to study neurochemistry with PET and will improve our ability to study both exogenous and endogenous stimuli.…”