Preclinical Imaging Evaluation of Novel TSPO-PET Ligand 2-(5,7-Diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1008) in Glioma

Tang, Dominic H.; Nickels, Michael L.; Tantawy, Mohammed Noor; Buck, Jason R.; Manning, H. Charles

doi:10.1007/s11307-014-0743-2

Cited by 31 publications

(36 citation statements)

References 32 publications

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“…The X-ray structure of compound 5A displayed the 5-methyl and 7-ethyl substitution patterns on the pyrazolopyrimidinal ring, while compound 5B displayed the reverse, 5-ethyl and 7-methyl. Reaction of 5A and 5B with tosylated fluoroethanol under microwave-assisted organic synthesis (MAOS) conditions [17–19] gave compounds 3A and 3B, respectively (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…[ 18 F]3A and [ 18 F]3B were prepared analogously to methods published in previous studies [17–19] (see Supplemental Information). …”

Section: Methodsmentioning

confidence: 99%

“…Plasma radiometabolites of [ 18 F]3A and [ 18 F]3B were evaluated using radio-thin-layer chromatography (radio-TLC) according to the published methods [19]. …”

Section: Methodsmentioning

confidence: 99%

“…In prior studies, we have shown that high-affinity, pyrazolopyrimidine TSPO PET probes such as [ 18 F]DPA-714 (1) [17] and [ 18 F]VUIIS1008 (2) [18, 19], as well as contemporary TSPO ligands based upon other unique scaffolds [20–22], can be used to visualize TSPO expression in tumors in preclinical settings (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging

Tang

Buck

et al. 2016

Mol Imaging Biol

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Purpose Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats. Procedures VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D 1H-15N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [18F]VUIIS1009A and [18F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [18F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry. Results Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC50 values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [18F]VUIIS1009A and [18F]VUIIS1009B exhibited greater binding potential (k3/k4) in tumor tissue compared to [18F]DPA-714. Interestingly, [18F]VUIIS1009B exhibited significantly greater tumor uptake (VT) than [18F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency. Conclusions The novel PET ligand [18F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [18F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [18F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

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Section: Resultsmentioning

confidence: 99%

“…[ 18 F]3A and [ 18 F]3B were prepared analogously to methods published in previous studies [17–19] (see Supplemental Information). …”

Section: Methodsmentioning

confidence: 99%

“…Plasma radiometabolites of [ 18 F]3A and [ 18 F]3B were evaluated using radio-thin-layer chromatography (radio-TLC) according to the published methods [19]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging

Tang

Buck

et al. 2016

Mol Imaging Biol

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“…1, 7–13 We previously optimized the 5, 6, and 7 positions of a pyrazolopyrimidine, DPA-713 6,14 and reported a novel fluorine-18-labeled PET tracer (VUIIS 1008) with improved affinity and pharmacokinetic properties for cancer imaging. 1,11 Based upon our prior work and motivated by the work of Selleri et al, 15 we further elaborated on the pyrazolopyrimidine structure activity relationships related to N,N -disubstitutions of the terminal acetamide (Figure 1). Herein, we report a variety of novel pyrazolopyrimidine TSPO candidate ligands (n = 16), bearing alkyl, alicyclic, aryl, and heterocyclic pendant acetamides.…”

mentioning

confidence: 99%

New structure–activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO

Schulte

Nickels

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized pyrazolopyrimidine scaffold, we elucidated new structure activity relationships related to N,N-disubstitutions of the terminal acetamide on pyrazolopyrimidines and further explored the impacts of these substituents on lipophilicity and plasma protein binding. Several novel chemical probes reported here exhibited significantly increased binding affinity, suitable lipophilicity and protein binding compared with contemporary TSPO ligands. We illustrate that N,N-acetamide disubstitution affords opportunities to introduce diverse chemical moieties distal to the central pyrazolopyrimidine core, without sacrificing TSPO affinity. We anticipate that further exploration of N-acetamide substitutions may yield additional TSPO ligands capable of furthering the field of precision medicine.

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Imaging the Host Response

et al. 2017

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Preclinical Imaging Evaluation of Novel TSPO-PET Ligand 2-(5,7-Diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1008) in Glioma

Cited by 31 publications

References 32 publications

Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging

Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging

New structure–activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO

Imaging the Host Response

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