Satish Chitneni

Overview:

The major focus of our research has been on the design, development and evaluation of novel radiotracers based on small molecules for imaging specific molecular targets using positron emission tomography (PET). The imaging targets are usually enzymes, cell surface receptors or transporters that are strongly implicated in or markers of diseases. Fluorine-18, which has a half-life of about 110 min, is ideally suited for radiolabeling of small molecules, and permits PET imaging studies for up to 4 h after injection in vivo. Other radioisotopes of interest for PET radiotracer development include carbon-11 and iodine-124, the latter one has a longer half-life (4.2 days) and enables imaging for up to 1 week after injection of the labeled probe. Another major area of interest include the use of PET imaging for evaluation of novel therapeutics in preclinical models of diseases.

Positions:

Associate Professor in Radiology

Radiology
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

Katholieke Universiteit Leuven (Belgium)

Grants:

Exercise-induced recovery of intervertebral disc health

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Exercise-induced recovery of intervertebral disc health

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Publications:

Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.

RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2). Herein we investigated the feasibility of developing 18F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7, were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene glycol (PEG3) or a propyl linker. The inhibitory potency (IC50) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next, compound 6 was labeled with 18F using a trimethylammonium triflate precursor to obtain [18F]FN-PEG3-RG7388 ([18F]6), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines (SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed an IC50 against MDM2 of 119 nM and 160 nM for 6 and 7, respectively. 18F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [18F]6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2 cell lines. Saturation binding assays revealed a binding affinity (Kd) of 128 nM for [18F]6 on SJSA-1 cells. In mice, [18F]6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ± 0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [18F]6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies in mice using HPLC showed ∼60% and ∼30% intact [18F]6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity attributed to polar peaks. Our results suggest that RG7388 is a promising molecular scaffold for 18F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the 18F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.
MLA Citation
Zhou, Zhengyuan, et al. “Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.Mol Pharm, vol. 18, no. 10, Oct. 2021, pp. 3871–81. Pubmed, doi:10.1021/acs.molpharmaceut.1c00531.
URI
https://scholars.duke.edu/individual/pub1497080
PMID
34523337
Source
pubmed
Published In
Mol Pharm
Volume
18
Published Date
Start Page
3871
End Page
3881
DOI
10.1021/acs.molpharmaceut.1c00531

Feasibility of Developing Radiotracers for MDM2: Synthesis and Preliminary Evaluation of an 18F-Labeled Analogue of the MDM2 Inhibitor SP-141.

Murine double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor protein, is overexpressed in several human cancers. Herein we investigate the feasibility of developing 18F-labeled compounds based on the small molecule inhibitor SP-141 for imaging tumor MDM2 expression levels with positron emission tomography (PET). Three nonradioactive fluorinated SP-141 analogues, 1-3, were synthesized, and their binding to the MDM2 protein was analyzed by surface plasmon resonance (SPR). One of these, a fluoroethoxy analogue, was labeled with fluorine-18 (18F) using 18F-fluorethyl bromide to provide [18F]1 and evaluated in vitro and in vivo. SPR analysis confirmed the binding of the fluorinated analogues to MDM2 at 1.25-20 µM concentrations. Cell uptake studies revealed high uptake (67.5-71.4%/mg protein) and specificity of [18F]1 in MCF7 and HepG2 cells. The uptake of [18F]1 in these cells could be modulated using 100 µM SP-141, potentially reflecting changes in MDM2 expression because of p53 activation by SP-141. [18F]1 exhibited stable uptake and retention in HepG2 tumor xenografts (~3 %ID/g) in vivo, but poor clearance from blood and other normal tissues, yielding low tumor-to-background ratios (<2) at 2 h post injection. Our results suggest that [18F]1 has suboptimal characteristics for in vivo evaluation as a PET tracer for MDM2, but warrant radiolabeling and assessment of the other fluorinated analogues synthesized in this work, 2 and 3, and potentially other molecular scaffolds for developing MDM2 targeted radiotracers.
MLA Citation
Chitneni, Satish K., et al. “Feasibility of Developing Radiotracers for MDM2: Synthesis and Preliminary Evaluation of an 18F-Labeled Analogue of the MDM2 Inhibitor SP-141.Pharmaceuticals (Basel), vol. 14, no. 4, Apr. 2021. Pubmed, doi:10.3390/ph14040358.
URI
https://scholars.duke.edu/individual/pub1478156
PMID
33924734
Source
pubmed
Published In
Pharmaceuticals (Basel, Switzerland)
Volume
14
Published Date
DOI
10.3390/ph14040358

Synthesis and preliminary biological evaluation of [F-18]JNJ41510417as a radioligand for positron emission tomography imaging of phosphodiesterase-10A in the brain

Authors
Celen, S; De Angelis, M; Chitneni, SK; Alcazar, J; Koole, M; Dedeurwaerdere, S; Steckler, T; Schmidt, M; Van Laere, K; Verbruggen, A; Langlois, X; Andres, JI; Bormans, G
MLA Citation
Celen, S., et al. “Synthesis and preliminary biological evaluation of [F-18]JNJ41510417as a radioligand for positron emission tomography imaging of phosphodiesterase-10A in the brain.” European Journal of Nuclear Medicine and Molecular Imaging, vol. 36, no. SUPPL 2, SPRINGER, 2009, pp. 236–236.
URI
https://scholars.duke.edu/individual/pub1436942
Source
wos
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
36
Published Date
Start Page
236
End Page
236

Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) occurs in the context of aberrant metabolism. Glutaminolysis is required for metabolic reprograming of hepatic stellate cells (HSCs) and liver fibrogenesis in mice. However, it is unclear how changes in HSC glutamine metabolism contribute to net changes in hepatic glutaminolytic activity during fibrosis progression, or whether this could be used to track fibrogenic activity in NASH. We postulated that increased HSC glutaminolysis marks active scarring in NASH. METHODS: Glutaminolysis was assessed in mouse NASH fibrosis models and in NASH patients. Serum and liver levels of glutamine and glutamate and hepatic expression of glutamine transporter/metabolic enzymes were correlated with each other and with fibrosis severity. Glutaminolysis was disrupted in HSCs to examine if this directly influenced fibrogenesis. 18F-fluoroglutamine positron emission tomography was used to determine how liver glutamine assimilation tracked with hepatic fibrogenic activity in situ. RESULTS: The serum glutamate/glutamine ratio increased and correlated with its hepatic ratio, myofibroblast content, and fibrosis severity. Healthy livers almost exclusively expressed liver-type glutaminase (Gls2); Gls2 protein localized in zone 1 hepatocytes, whereas glutamine synthase was restricted to zone 3 hepatocytes. In fibrotic livers, Gls2 levels reduced and glutamine synthase zonality was lost, but both Slc1a5 (glutamine transporter) and kidney-type Gls1 were up-regulated; Gls1 protein was restricted to stromal cells and accumulated in fibrotic septa. Hepatocytes did not compensate for decreased Gls2 by inducing Gls1. Limiting glutamine or directly inhibiting GLS1 inhibited growth and fibrogenic activity in cultured human HSCs. Compared with healthy livers, fibrotic livers were 18F-fluoroglutamine-avid by positron emission tomography, suggesting that glutamine-addicted myofibroblasts drive increased hepatic utilization of glutamine as fibrosis progresses. CONCLUSIONS: Glutaminolysis is a potential diagnostic marker and therapeutic target during NASH fibrosis progression.
Authors
Du, K; Chitneni, SK; Suzuki, A; Wang, Y; Henao, R; Hyun, J; Premont, RT; Naggie, S; Moylan, CA; Bashir, MR; Abdelmalek, MF; Diehl, AM
MLA Citation
Du, Kuo, et al. “Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression.Cell Mol Gastroenterol Hepatol, vol. 10, no. 1, 2020, pp. 1–21. Pubmed, doi:10.1016/j.jcmgh.2019.12.006.
URI
https://scholars.duke.edu/individual/pub1416470
PMID
31881361
Source
pubmed
Published In
Cellular and Molecular Gastroenterology and Hepatology
Volume
10
Published Date
Start Page
1
End Page
21
DOI
10.1016/j.jcmgh.2019.12.006

Observations on the Effects of Residualization and Dehalogenation on the Utility of N-Succinimidyl Ester Acylation Agents for Radioiodination of the Internalizing Antibody Trastuzumab.

Trastuzumab is an antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers. Since trastuzumab is an internalizing antibody, two factors could play an important role in achieving high uptake and prolonged retention of radioactivity in HER2-positive tumors after radioiodination-residualizing capacity after receptor-mediated internalization and susceptibility to dehalogenation. To evaluate the contribution of these two factors, trastuzumab was radiolabeled using the residualizing reagent N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB) and the nonresidualizing reagent N-succinimidyl-3-[*I]iodobenzoate ([*I]SIB), both of which are highly dehalogenation-resistant. Paired-label uptake and intracellular retention of [125I]SGMIB-trastuzumab and [131I]SIB-trastuzumab was compared on HER2-expressing BT474 human breast carcinoma cells. Tumor uptake and normal tissue distribution characteristics for the two labeled conjugates were assessed in mice bearing BT474M1 xenografts. The internalization and intracellular retention of initially-bound radioactivity in BT474 cells was similar for the two labeled conjugates up to 4 h, but were significantly higher for [125I]SGMIB-trastuzumab at 6 and 24 h. Similarly, [*I]SGMIB labeling resulted in significantly higher uptake and retention of radioactivity in BT474M1 xenografts at all studied time points. Moreover, tumor-to-tissue ratios for [125I]SGMIB-trastuzumab were consistently higher than those for [131I]SIB-trastuzumab starting at 12 h postinjection. Thus, optimal targeting of HER2-positive breast cancers with a radioiodinated trastuzumab conjugate requires an acylation agent that imparts residualizing capacity in addition to high stability towards dehalogenation in vivo.
Authors
MLA Citation
URI
https://scholars.duke.edu/individual/pub1417559
PMID
31671554
Source
pubmed
Published In
Molecules (Basel, Switzerland)
Volume
24
Published Date
DOI
10.3390/molecules24213907

Research Areas:

Animals
Anoxia
Antigens, Neoplasm
Benzimidazoles
Bicyclo Compounds
Bicyclo Compounds, Heterocyclic
Biological Transport
Brain
Bridged Bicyclo Compounds
Bridged Bicyclo Compounds, Heterocyclic
Carbon Radioisotopes
Carbonic Anhydrases
Carboxylic Acids
Cell Line
Cell Line, Tumor
Cell Transformation, Neoplastic
Chemistry Techniques, Synthetic
Chromatography, High Pressure Liquid
Cocaine
Cyclic N-Oxides
Disease Models, Animal
Dopamine Plasma Membrane Transport Proteins
Drug Evaluation, Preclinical
Esters
Female
Fetus
Fluorine Radioisotopes
Follow-Up Studies
Gene Expression
Gene Transfer Techniques
Genes, Reporter
Genetic Therapy
Genetic Vectors
HEK293 Cells
Herpesvirus 3, Human
Homeostasis
Humans
Hypoxia
Immunohistochemistry
Intracellular Space
Isotope Labeling
Kidney
Kinetics
Lac Operon
Lentivirus
Ligands
Liver
Lung
Lung Neoplasms
Magnetic Resonance Spectroscopy
Male
Metabolic Clearance Rate
Mice
Misonidazole
Models, Chemical
Molecular Imaging
Molecular Structure
Molecular Targeted Therapy
Necrosis
Neoplasms
Neovascularization, Pathologic
Nitroimidazoles
Nucleosides
Nucleotides, Cyclic
Oligopeptides
Organ Specificity
Organotechnetium Compounds
Phosphoric Diester Hydrolases
Phosphorylation
Positron-Emission Tomography
Pregnancy
Pregnancy, Animal
Prodrugs
Prostatic Neoplasms
Pyrans
Pyrazoles
Pyrimidine Nucleosides
Quinolines
Radioisotopes
Radiopharmaceuticals
Rats
Rats, Wistar
Reactive Oxygen Species
Reproducibility of Results
Rhenium
Sensitivity and Specificity
Signal Transduction
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Sulfonamides
Thymidine Kinase
Time Factors
Tissue Distribution
Transduction, Genetic
Treatment Outcome
Triazines
Tumor Markers, Biological
Viral Load
Xenograft Model Antitumor Assays