Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

Abstract

Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

“…These changes coincide with reduced protein and/or mRNA levels of various synaptic markers [5][6][7][8][9][10][11] . Whereas the majority of these data were derived from post-mortem human material, the recent development of the UCB-J PET tracers, which specifically interact with the presynaptic Synaptic Vesicle glycoprotein 2A (SV2A), has enabled visualisation of pre-synaptic terminal density in the living human brain [12][13][14] . SV2A is thought to play a role in neurotransmitter release and vesicle recycling [15][16][17][18] , and, due its localisation at both inhibitory and excitatory synapses throughout the brain, is considered as a proxy for overall synaptic density.…”

PET Radiotracers for CNS-Adrenergic Receptors: Developments and Perspectives

“…Among the PET isotopes, cyclotron produced carbon-11 (C-11, t 1/2 = 20.34 min), nitrogen-13 (N-13, t 1/2 = 9.96 min), and fluorine-18 (F-18, t 1/2 = 109.77 min) are frequently used for PET-neuroimaging. PET imaging is particularly valuable to characterize investigational drugs and their target proteins, providing a valuable tool for clinical neuroscience [ 3 ].…”

“…PET radiotracers for the central nervous system (CNS) should have proper pharmacokinetic profile in the brain and to achieve this property, they were designed to meet five molecular properties: (a) molecular weight <500 kDa, (b) Log D 7.4 between ~1 to 3 (lipophilicity factor), (c) number of hydrogen bond donors <5, (d) number of hydrogen bond acceptors <10, and (e) topological polar surface area <90 Å 2 . Otherwise, they may either not cross the blood-brain barrier (BBB) or show lack of specific signal due to high nonspecific binding [ 3 , 4 , 5 ]. In addition, an ideal PET radiotracer should have, though unachievable, (a) high affinity (preferably subnanomolar range) for its target, (b) high selectivity between subtypes or void on off-targets, (c) high dynamic range in specific binding, (d) appropriate metabolic profile, (e) no adverse toxicology effects, and (f) kinetics suitable for mathematical modelling, which requires fast transfer to BBB and clearance in non-target tissues [ 3 ].…”

“…Otherwise, they may either not cross the blood-brain barrier (BBB) or show lack of specific signal due to high nonspecific binding [ 3 , 4 , 5 ]. In addition, an ideal PET radiotracer should have, though unachievable, (a) high affinity (preferably subnanomolar range) for its target, (b) high selectivity between subtypes or void on off-targets, (c) high dynamic range in specific binding, (d) appropriate metabolic profile, (e) no adverse toxicology effects, and (f) kinetics suitable for mathematical modelling, which requires fast transfer to BBB and clearance in non-target tissues [ 3 ]. In general, a radiotracer with binding potential [ratio of target density ( B max ) to ligand’s affinity ( K d or K i )] value of at least 10 is expected to provide a reliable specific signal in vivo [ 6 , 7 ].…”

“…Furthermore, there are some technical challenges associated with CNS PET radiotracer development, which include: limited synthesis time and/or complex syntheses to prepare a radiotracer, attainment of high molar activity, accurate radiometric metabolite analysis. In addition, the radiotracer ought to ideally address targets that are relevant to brain function and for the diagnosis and therapy of a disease [ 3 , 8 ]. Epinephrine (E) and norepinephrine (NE) were discovered in 1894 and 1907, respectively.…”