RT Journal Article
SR Electronic
T1 Direct Imaging of Drug Distribution and Target Engagement of the PARP Inhibitor Rucaparib
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1316
OP 1320
DO 10.2967/jnumed.117.205765
VO 59
IS 8
A1 Susanne Kossatz
A1 Brandon Carney
A1 Christopher Farley
A1 Wolfgang A. Weber
A1 Charles M. Drain
A1 Thomas Reiner
YR 2018
UL http://jnm.snmjournals.org/content/59/8/1316.abstract
AB Poly(ADP-ribose)polymerase (PARP) inhibitors have emerged as potent antitumor drugs. Here, we describe the intrinsic fluorescence properties of the clinically approved PARP inhibitor rucaparib and its potential to directly measure drug distribution and target engagement—a critical factor for understanding drug action and improving efficacy. Methods: We characterized the photophysical properties of rucaparib and determined its quantum yield and lifetime. Using confocal microscopy and flow cytometry, we imaged the intracellular distribution of rucaparib and measured uptake and release kinetics. Results: Rucaparib has an excitation/emission maximum of 355/480 nm and a quantum yield of 0.3. In vitro time-lapse imaging showed accumulation in cell nuclei within seconds of administration. Nuclear rucaparib uptake increased with higher PARP1 expression, and we determined an intracellular half-life of 6.4 h. Conclusion: The label-free, intrinsic fluorescence of rucaparib can be exploited to interrogate drug distribution and target binding, critical factors toward improving treatment efficacy and outcome.