A peptide-based positron emission tomography probe for in vivo detection of caspase activity in apoptotic cells.

Hight MR, Cheung YY, Nickels ML, Dawson ES, Zhao P, Saleh S, Buck JR, Tang D, Washington MK, Coffey RJ, Manning HC
Clin Cancer Res. 2014 20 (8): 2126-35

PMID: 24573549 · PMCID: PMC3989451 · DOI:10.1158/1078-0432.CCR-13-2444

PURPOSE - Apoptosis, or programmed cell death, can be leveraged as a surrogate measure of response to therapeutic interventions in medicine. Cysteine aspartic acid-specific proteases, or caspases, are essential determinants of apoptosis signaling cascades and represent promising targets for molecular imaging. Here, we report development and in vivo validation of [(18)F]4-fluorobenzylcarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone ([(18)F]FB-VAD-FMK), a novel peptide-based molecular probe suitable for quantification of caspase activity in vivo using positron emission tomography (PET).

EXPERIMENTAL DESIGN - Supported by molecular modeling studies and subsequent in vitro assays suggesting probe feasibility, the labeled pan-caspase inhibitory peptide, [(18)F]FB-VAD-FMK, was produced in high radiochemical yield and purity using a simple two-step, radiofluorination. The biodistribution of [(18)F]FB-VAD-FMK in normal tissue and its efficacy to predict response to molecularly targeted therapy in tumors was evaluated using microPET imaging of mouse models of human colorectal cancer.

RESULTS - Accumulation of [(18)F]FB-VAD-FMK was found to agree with elevated caspase-3 activity in response to Aurora B kinase inhibition as well as a multidrug regimen that combined an inhibitor of mutant BRAF and a dual PI3K/mTOR inhibitor in (V600E)BRAF colon cancer. In the latter setting, [(18)F]FB-VAD-FMK PET was also elevated in the tumors of cohorts that exhibited reduction in size.

CONCLUSIONS - These studies illuminate [(18)F]FB-VAD-FMK as a promising PET imaging probe to detect apoptosis in tumors and as a novel, potentially translatable biomarker for predicting response to personalized medicine.

©2014 AACR.

MeSH Terms (28)

Amino Acid Chloromethyl Ketones Animals Apoptosis Caspase 3 Caspase Inhibitors Cell Line, Tumor Colonic Neoplasms Colorectal Neoplasms Female Fluorine Radioisotopes Fluorobenzenes Humans Imidazoles Immunoblotting Immunohistochemistry Indoles Mice, Inbred C57BL Mice, Nude Organophosphates Peptides Positron-Emission Tomography Protein Kinase Inhibitors Quinazolines Quinolines Radiopharmaceuticals Sulfonamides Tissue Distribution Xenograft Model Antitumor Assays

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