Measurement of Bmax and Kd 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 (Kd) and target concentration (Bmax) images, constraining Kd to be uniform across the brain. This paradigm was tested with (18)F-MK6577 in baboons. Voxel-based analysis produced high quality Bmax images and reliable Kd estimates, and also suggested that the nondisplaceable distribution volume (VND) is not uniform throughout the brain. In vivo GlyT1 Kd 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 Kd and Bmax values agreed well with those determined in vitro, thus validating our novel multi-infusion approach.

• Authors: Yan Xia, Ming-Qiang Zheng, Daniel Holden, Shu-fei Lin, Michael Kapinos, Jim Ropchan, Jean-Dominique Gallezot, Yiyun Huang, Richard E Carson
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 35 Issue 12 Pg. 2001-9 (Dec 2015) ISSN: 1559-7016 [Electronic] United States
• PMID: 26198176 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzamides
• Glycine Plasma Membrane Transport Proteins
• MK-6577
• Radiopharmaceuticals
• Sulfonamides

Topics

• Algorithms
• Animals
• Benzamides (administration & dosage, blood, pharmacokinetics)
• Biotransformation
• Brain (diagnostic imaging, metabolism)
• Cerebellum (diagnostic imaging, metabolism)
• Glycine Plasma Membrane Transport Proteins (metabolism)
• Image Processing, Computer-Assisted
• Infusions, Intravenous
• Magnetic Resonance Imaging
• Papio (metabolism)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (administration & dosage, blood, pharmacokinetics)
• Sulfonamides (administration & dosage, blood, pharmacokinetics)