Synthesis and preliminary biological evaluation of [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate for the fractalkine receptor (CX3CR1)

Abstract

Abstract-TheCX3C chemokine receptor 1 (CX3CR1), also known as fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a protein in humans. 1 CX3CR1 binds the chemokine CX3CL1, also called fractalkine ligand or neurotactin. 2 CX3CR1 is expressed in the brain, spleen, and in subpopulations of leukocytes, cells of monocytic lineage, and neutrophils but also in lymphocytes, and associated with various cancer, cardiovascular and neurological diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). 3 CX3CR1 is an interesting therapeutic target, and many selective CX3CR1 antagonists have been developed. 4,5 Methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-Dleucinate (5) recently developed by AstraZeneca is a potent and selective CX3CR1 antagonist with Ki 8.3 and 1940 nM for CX3CR1 and CXCR2, respectively, and selectivity index (SI) 230. 6 CX3CR1 has also become a promising target for molecular imaging of CX3CR1-mediated diseases and image-guided therapy using positron emission tomography (PET) modality. However, radionuclides including carbon-11 and fluorine-18 labeled CX3CR1 antagonists are still not reported. In our previous work, we have developed carbon-11-labeled naphthalene-sulfonamides as potential radioligands for PET imaging of chemokine receptor 8 (CCR8), as indicated in Figure 1. 7 In this ongoing study, we first target CX3CR1 and develop radiolabeled CX3CR1 antagonists. Here we report the synthesis and preliminary biological evaluation of

PET Imaging of Neuroinflammation in Alzheimer’s Disease

“…Mitochondrial 18 kDa translocator protein (TSPO) is the most widely investigated neuroinflammation target for PET imaging ( 36 ). Other alternative targets are under rapid development ( Table 1 ), such as monoamine oxidase-B (MAO-B), matrix metalloproteinases ( 144 – 147 , 185 , 186 ), colony-stimulating factor 1 receptor (CSF1R), imidazoline-2 binding sites (I 2 BS), cyclooxygenases, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, reactive oxygen species, cannabinoid-2 receptor, purinergic P2X7 receptor and P2Y12 receptor, the fractalkine receptor (CX3CR1) ( 187 ), TREM2 ( 140 ), and receptor for advanced glycation end products ( 36 , 188 ) ( Table 1 ).…”

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica

“…Moreover, low non-specific brain uptake and low blood radioactivity may be beneficial for imaging both LV-GCA and C-GCA. On the other hand, the radiotracer [ 11 C]methyl(2-amino-5(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate designed to target CX3CR1, failed to show specific binding to CX3CR1 and therefore is not suitable for imaging GCA at the current state ( 303 ). As CX3CR1+ monocyte infiltration was reported to be higher than CCR2+ monocytes, future radiotracers targeting CX3CR1 may be beneficial for the imaging of GCA.…”

PET Imaging Radiotracers of Chemokine Receptors

“…Around the year 2013, AstraZeneca had developed a series of CX 3 CR1-selective antagonists based on a 7-Amino-5-thio-thiazolo[4,5- d ]pyrimidine core, using SAR studies and h CX 3 CR1 cell assays [ 63 ]. Based on this, Gao et al, in 2017 prepared 31 with MA 370–1110 GBq/μmol at the EOB ( Figure 15 ) [ 145 ]. Radiotracer 31 was prepared using C-11 methylation from the corresponding carboxylic acid precursor.…”