The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing

Abstract

Translocator protein (TSPO, 18 kDa) is an evolutionary, well-preserved, and tryptophan-rich 169-amino-acid protein which localizes on the contact sites between the outer and inner mitochondrial membranes of steroid-synthesizing cells. This mitochondrial protein is implicated in an extensive range of cellular activities, including steroid synthesis, cholesterol transport, apoptosis, mitochondrial respiration, and cell proliferation. The upregulation of TSPO is well documented in diverse disease conditions including neuroinflammation, cancer, brain injury, and inflammation in peripheral organs. On the basis of these outcomes, TSPO has been assumed to be a fascinating subcellular target for early stage imaging of the diseased state and for therapeutic purposes. The main outline of this Review is to give an update on dealing with the advances made in TSPO PET tracers for neuroinflammation, synchronously emphasizing the approaches applied for the design and advancement of new tracers with reference to their structure–activity relationship (SAR).

[18F]BIBD-239: 18F-Labeled ER176, a Positron Emission Tomography Tracer Specific for the Translocator Protein

“…14−20 [ 11 C]PK11195, as the first and most classic TSPO-targeting tracer, has been widely used in the diagnosis of various clinical diseases, especially in monitoring the process of central nervous system diseases. 21,22 However, limitations of low sensitivity and high nonspecific binding of [ 11 C]PK11195 led to the development of a series of second-generation tracers with improved characterization, such as [ 11 C]PBR28, [ 11 C]DPA-713, [ 18 F]DPA-714, [ 18 F]PBR06, [ 18 F]FEPPA, [ 11 C]DAA1106, and so forth. 23−39 The second-generation tracers show higher specificity to TSPO and better pharmacokinetics, but most of them are sensitive to the single-nucleotide polymorphism (SNP) rs6971 in the TSPO gene, which causes an alanine (Ala)-to-threonine (Thr) substitution in position 147.…”

“…43,44 The diversity requires genotyping before TSPO imaging; otherwise, it will result in inaccurate quantification. To overcome the variability of binding affinity, third-generation PET tracers, with less sensitivity to TSPO SNP, have been developed, such as [ 18 F]GE-180, [ 18 F]LW223, and [ 11 C]ER176. 45−48 However, the clinical application of [ 18 F]GE-180 is limited due to its poor brain penetration and stability in vivo.…”

“…Recently, Pike et al reported [ 18 F]3b based on the structure of ER176 (Figure 1), but the labeling conditions of this compound are harsh and the clinical results are unknown. 50,51 Therefore, 18 F-labeled PET tracers which are not sensitive to the TSPO genotype polymorphism are still being developed. Here, we report a new TSPO-targeting tracer [ 18 F]BIBD-239 by modifying the structure of ER176.…”

“…50,51 Therefore, 18 F-labeled PET tracers which are not sensitive to the TSPO genotype polymorphism are still being developed. Here, we report a new TSPO-targeting tracer [ 18 F]BIBD-239 by modifying the structure of ER176. This tracer was further evaluated through in vitro binding assays and autoradiography, theoretical calculations, and PET imaging to diagnose stroke focus and glioma using animal disease models.…”

“…Radiolabeling. [ 18 F]Fluoride solution in [ 18 O]H 2 O was purchased from HTA Co., Ltd. Solid-phase extraction cartridges such as Sep-Pak QMA Light and Oasis HLB cartridges were purchased from Waters (Milford, MA). High-performance liquid chromatography (HPLC) was performed on an Agilent 1100 series system with different HPLC columns.…”