Comparison of four (11)C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios.

Translocator protein (TSPO) is a biomarker for detecting neuroinflammation by PET. (11)C-(R)-PK11195 has been used to image TSPO since the 1980s. Here, we compared the utility of four (11)C-labeled ligands-(R)-PK11195, PBR28, DPA-713, and ER176-to quantify TSPO in healthy humans. For all of these ligands, BP ND (specific-to-non-displaceable ratio of distribution volumes) was measured by partially blocking specific binding with XNBD173 administration. In high-affinity binders, DPA-713 showed the highest BP ND of 7.3 followed by ER176 (4.2), PBR28 (1.2), and PK11195 (0.8). Only ER176 allows the inclusion of low-affinity binders because of little influence of radiometabolites and high BP ND. If inclusion of all three genotypes is important for study logistics, ER176 is the best of these four radioligands for studying neuroinflammation

(11)C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than (11)C-( R)-PK11195

Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent (11)C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the "signal to background" ratio (assessed as binding potential ( BPND)) of (11)C-( R)-PK11195 compared to one of the most promising second-generation radioligands, (11)C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either (11)C-( R)-PK11195 (16 subjects) or (11)C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30-90 mg PO). (11)C-DPA-713 showed a significant sensitivity to genotype in brain, whereas (11)C-( R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of (11)C-DPA-713 was much greater than that of (11)C-( R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for (11)C-DPA-713 (7.3) than for (11)C-( R)-PK11195 (0.75). Although the high specific binding of (11)C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain

Candidate 3-benzazepine-1-ol type GluN2B receptor radioligands (11C-NR2B-Me enantiomers) have high binding in cerebellum but not to σ1 receptors

Key points Question: Do GluN2B radioligands 11C-NR2B-Me enantiomers show cross-binding with σ1 receptors in brain in vivo? Pertinent findings: 11C-(+)-NR2B-Me, 11C-(−)-NR2B-Me, 11C-(S)-NR2B-SMe, and 11C-(R)-NR2B-SMe give specific signals in whole rat brain that could be pre-blocked and displaced using ligands that specifically target GluN2B receptors, but not by σ1 ligand FTC-146. Implications for patient care: 11C-(−)-NR2B-Me does not show cross-binding with σ1 receptor in rat brain using PET imaging. This radioligand may be promising for human PET imaging

11C-ER176, a radioligand for 18-kDa translocator protein (TSPO), has adequate sensitivity to robustly image all three affinity genotypes in human brain

For positron emission tomography (PET) imaging of 18-kDa translocator protein (TSPO), a biomarker of neuroinflammation, most second-generation radioligands are sensitive to the single nucleotide polymorphism rs6971; however this is probably not the case for the prototypical agent (11)C-PK 11195, which has a relatively lower signal-to-noise ratio. We recently found that (11)C-ER176, a new analog of (11)C-(R)-PK 11195, showed little sensitivity to rs6971 when tested in vitro and had high specific binding in monkey brain. This study sought: 1) to determine whether the sensitivity of (11)C-ER176 in human subjects was similar to the low sensitivity measured in vitro, and 2) to measure the binding potential (BPND), the ratio of specific to nondisplaceable uptake, of (11)C-ER176 in human brain

Microfluidics for Positron Emission Tomography Probe Development

Owing to increased needs for positron emission tomography (PET), high demands for a wide variety of radiolabeled compounds will have to be met by exploiting novel radiochemistry and engineering technologies to improve the production and development of PET probes. The application of microfluidic reactors to perform radiosyntheses is currently attracting a great deal of interest because of their potential to deliver many advantages over conventional labeling systems. Microfluidics-based radiochemistry can lead to the use of smaller quantities of precursors, accelerated reaction rates, and easier purification processes with greater yield and higher specific activity of desired probes. Several proof-of-principle examples along with the basics of device architecture and operation and the potential limitations of each design are discussed. Along with the concept of radioisotope distribution from centralized cyclotron facilities to individual imaging centers and laboratories (“decentralized model”), an easy-to-use, stand-alone, flexible, fully automated, radiochemical microfluidic platform can provide simpler and more cost-effective procedures for molecular imaging using PET

Synthesis and preclinical evaluation of [11C]uPSEM792 for PSAM4-GlyR based chemogenetics

Abstract Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM4 is a triple mutant PSAM derived from the α7 nicotinic receptor (α7L131G,Q139L,Y217F). Although having no constitutive activity as a ligand-gated ion channel, PSAM4 has been coupled to the serotonin 5-HT3 receptor (5-HT3R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM4-5-HT3 or PSAM4-GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM4-GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (t 1/2 = 20.4 min), in high radiochemical yield by treating a protected precursor with [11C]iodomethane followed by base deprotection. PET experiments with [11C]uPSEM792 in rodents and in a monkey transduced with PSAM4-GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood–brain barrier. These findings can inform the design of a more effective PSAM4 based PET radioligand, based on the uPSEM792 chemotype

[11C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

Previous work found that [C]deschloroclozapine ([C]DCZ) is superior to [C]clozapine ([C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hMDi) was injected into the right amygdala of a male rhesus macaque. [C]DCZ and [C]CLZ PET scans were conducted 2-24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [C]DCZ signal was 19% of that for [C]CLZ, and background uptake was 10% of that for [C]CLZ. Despite stronger [C]CLZ binding, the signal-to-background ratio for [C]DCZ was almost two-fold greater than for [C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%-50% for both radioligands. Thus, the greater signal-to-background ratio of [C]DCZ was due to its lower background uptake