In Vivo Receptor Visualization and Evaluation of Receptor Occupancy with Positron Emission Tomography

Abstract

Positron emission tomography (PET) is useful for noninvasive in vivo visualization of disease-related receptors, for evaluation of receptor occupancy to determine an appropriate drug dosage, and for proof-of-concept of drug candidates in translational research. For these purposes, the specificity of the PET tracer for the target receptor is critical. Here, we review work in this area, focusing on the chemical structures of reported PET tracers, their K i/K d values, and the physical properties relevant to target receptor selectivity. Among these physical properties, such as cLogP, cLogD, molecular weight, topological polar surface area, number of hydrogen bond donors, and pK a, we focus especially on LogD and LogP as important physical properties that can be easily compared across a range of studies. We discuss the success of PET tracers in evaluating receptor occupancy and consider likely future developments in the field.

Discovery of a highly specific 18F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination

“…Positron emission tomography (PET) imaging with highly specific radioligands 28 would enable noninvasive quantification of PDE10A, providing the opportunity to assess the function of PDE10A in vivo under physiological and pathophysiologic conditions 29 , 30 . Furthermore, dose–response experiments derived from PET would provide critical information on target occupancy of a candidate inhibitor at an administrated dose 31 , 32 , which would contribute to appropriate dosing with PDE10A inhibitors in early drug development, thereby ensuring sufficient exposure for efficacy and concurrently optimizing the risk-benefit profile of novel PDE10A inhibitors 33 , 34 . So far, several 11 C-labeled PDE10A radioligands were developed for imaging PDE10A in the living brain, such as [ 11 C]MP-10 ([ 11 C] 1 ) 35 , [ 11 C]IMA-107 ([ 11 C] 2 ) 36 , 37 , 38 , 39 , [ 11 C]Lu AE92686 ([ 11 C] 3 ) 40 , 41 and [ 11 C]T-773 33 ([ 11 C] 4 ) ( Fig.…”

PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84

“…Neuroinflammation is one of the cardinal features of multiple central nervous system (CNS) diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), and stroke. − Brain-innate immune dysfunction upregulates a plethora of receptors or biomarkers that can serve as a barometer of neuroinflammation. , Positron emission tomography (PET)a highly sensitive molecular imaging modalityis well suited to measure these biomarkers, expressed on innate immune cells at low concentrations . Accurate quantification of neuroinflammation via PET requires reliable biomarkers.…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…Furthermore, PET is also a versatile tool in evaluating the pharmacokinetic and pharmacodynamics properties of drug candidates in translational research, including determination of the receptor occupancy and drug dosage. 8 In general, the radioligand should have high specific binding signals in vivo (total/nonspecific ≥ 1.5) to allow quantitative mapping of its intended pharmacological target. For CNS PET imaging, most brain targets have low expression levels, and thus, related PET ligands typically demand a high in vitro binding potential (BP, defined as B max /K d ≥ 10), where B max is the maximum concentration of target binding sites and K d is the equilibrium constant.…”

“…In brain imaging, PET is useful for in vivo visualization of neuroreceptors (distribution and density) and/or localizing disease-related proteins, for example, amyloid-β plaques and Tau protein in Alzheimer’s disease (AD). Furthermore, PET is also a versatile tool in evaluating the pharmacokinetic and pharmacodynamics properties of drug candidates in translational research, including determination of the receptor occupancy and drug dosage . In general, the radioligand should have high specific binding signals in vivo (total/nonspecific ≥ 1.5) to allow quantitative mapping of its intended pharmacological target.…”

“…With regard to the chemical structure, a CNS PET ligand should contain a chemical group that is amenable for 11 C or 18 F incorporation (for more information about radiolabeling strategies, please refer to ref ). Finally, the CNS PET ligands should also fulfill the following requirements: high in vitro permeability and optimal lipophilicity (shake-flask log D ranged from 1.5 to 3.5) to facilitate blood–brain barrier (BBB) penetration and avoid high nonspecific binding and unfavorable brain efflux (efflux ratio ≤ 2) caused by, for example, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). − In this context, a large number of PET radioligands have been developed for “visualizing” 5-HTRs’ biodistribution and expression in physiological and/or pathological conditions, and many clinical achievements have been made with several excellent PET tracers. Compared with existing review articles, − this Perspective provides a comprehensive account of 5-HTR PET ligands by focusing on their chemotypes and PET imaging outcomes.…”