Synthesis and Biological Evaluation of Substituted [¹⁸F]Imidazo[1,2-a]pyridines and [¹⁸F]Pyrazolo[1,5-a]pyrimidines for the Study of the Peripheral Benzodiazepine Receptor Using Positron Emission Tomography

Abstract

The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

“…These include the atypical benzodiazepine [ 11 C]Ro5-4864 [8], the vinca alkaloid [ 11 C]Vinpocetine [9], dihydro-9H-purinacetamides (for example, N -benzyl- N -ethyl-2-(7-[ 11 C]methyl-8-oxo-2-phenylpurin-9-yl)acetamide, known as [ 11 C]Emapunil [10]), aryloxyanilides (such as [ 11 C]PBR28 [11] and [ 18 F]FEPPA [12]), indoleacetamides (such as [ 18 F]GE-180 [13] and [ 11 C]SSR180575 [14]), acetamidobenzoxazolones [15] without forgetting pyrazolopyrimidines, and bioisoteric structures (imidazopyridines, for example). The latter classes indeed include an impressive list of PET-radioligands, among them, the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides [ 11 C]DPA-713 [16], [ 18 F]DPA-714 [17], and [ 18 F]PBR146 [18], and the 6-chloro-imidazo[1,2-a]pyridin-3-yl)acetamides [ 11 C]CLINME [19], [ 18 F]PBR102 [18] and [ 18 F]PBR111 [20]. …”

Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists

“…Treatment of substituted acetophenone 2 with bromine in the presence of AlCl 3 in Et 2 O (Bunders et al 2010) afforded á-bromomethylketone 3. Subsequently, 3 and the substituted 2-aminopyridines 4 , 5 were allowed to react in the presence of sodium bicarbonate in refluxing ethanol (Fookes et al 2008), resulting in the generation of compounds 6a and 6b. The deacetylation of compounds 6a and 6b with sodium hydroxide afforded compounds 7a and 7b, respectively.…”

Double Application of Translocator Protein Ligands and RAW Cells Inflammatory Milieu

“…The selected TSPO ligands were synthesized as previously described (Katsifis et al, 2000;2004;Homes et al, 2006;Fookes et al, 2008) and their chemical structures and affinity for TSPO and the central Benzodiazepine Receptor (CBR) are shown in the Fig. 1 The isoquinoline carboxamide PK11195 and the benzodiazepine Ro5-4864 were purchased from Sigma-Aldrich.…”

“…This broad spectrum of bioactivities makes it an attractive theurapeutic drug target and a number of TSPO ligands has been synthesised and evaluated for their functional effects on TSPO and development of potential therapeutic agents (Szewczyk and Wojtczak, 2002;Galiegue et al, 2003;Karlstetter et al, 2014;Selvaraj et al, 2015). In addition, the development of radiolabelled TSPO ligands as molecular markers for imaging (Katsifis et al, 2000;Fookes et al, 2008;Pulli and Chen, 2014;Katsifis et al, 2004) helped localizing and monitoring the TSPO upregulation on activated microglia and/or astrocytes which is one of the hallmarks of neuroinflammation and neurodegeneration (Wilms et al, 2003;Girard et al, 2008;Mattner et al, 2011;Daugherty et al, 2013;Mattner et al, 2013).…”