Imaging Therapeutic PARP Inhibition In Vivo through Bioorthogonally Developed Companion Imaging Agents

• Published in: Neoplasia (New York, N.Y.) Vol. 14; no. 3; pp. 169 - IN3
• Main Authors: Reiner, Thomas, Lacy, Jessica, Keliher, Edmund J, Yang, Katherine S, Ullal, Adeeti, Kohler, Rainer H, Vinegoni, Claudio, Weissleder, Ralph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2012; Elsevier
• Subjects: Animals; Catalytic Domain; Cell Line, Tumor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Models, Molecular; Molecular Imaging; Multimodal Imaging; Neoplasms - diagnosis; Neoplasms - drug therapy; Oncology; Phthalazines - chemistry; Phthalazines - metabolism; Phthalazines - pharmacology; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - chemistry; Positron-Emission Tomography; Protein Binding; Protein Conformation; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacology; Tomography, X-Ray Computed
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.12414

A number of small-molecule poly (ADP-ribose) polymerase (PARP) inhibitors are currently undergoing advanced clinical trials. Determining the distribution and target inhibitory activity of these drugs in individual subjects, however, has proven problematic. Here, we used a PARP agent for positron emission tomography-computed tomography (PET-CT) imaging (18 F-BO), which we developed based on the Olaparib scaffold using rapid bioorthogonal conjugation chemistries. We show that the bioorthogonal18 F modification of the parent molecule is simple, highly efficient, and well tolerated, resulting in a half maximal inhibitory concentration (IC50 ) of 17.9 ± 1.1 nM. Intravital imaging showed ubiquitous distribution of the drug and uptake into cancer cells, with ultimate localization within the nucleus, all of which were inhibitable. Whole-body PET-CT imaging showed tumoral uptake of the drug, which decreased significantly, after a daily dose of Olaparib. Standard18 F-fludeoxyglucose imaging, however, failed to detect such therapy-induced changes. This research represents a step toward developing a more generic approach for the rapid codevelopment of companion imaging agents based on small-molecule therapeutic inhibitors.