PT  - JOURNAL ARTICLE
AU  - Igal Madar
AU  - Yi Huang
AU  - Hayden Ravert
AU  - Susan L. Dalrymple
AU  - Nancy E. Davidson
AU  - John T. Isaacs
AU  - Robert F. Dannals
AU  - J. James Frost
TI  - Detection and Quantification of the Evolution Dynamics of Apoptosis Using the PET Voltage Sensor <sup>18</sup>F-Fluorobenzyl Triphenyl Phosphonium
AID  - 10.2967/jnumed.108.061283
DP  - 2009 May 01
TA  - Journal of Nuclear Medicine
PG  - 774--780
VI  - 50
IP  - 5
4099  - http://jnm.snmjournals.org/content/50/5/774.short
4100  - http://jnm.snmjournals.org/content/50/5/774.full
SO  - J Nucl Med2009 May 01; 50
AB  - Apoptosis is a key mechanism in numerous pathologies. However, there are no effective noninvasive means available for an early detection and quantitative assessment of evolution dynamics of the apoptotic process. Here, we have characterized the ability of the novel PET voltage sensor 18F-fluorobenzyl triphenyl phosphonium (18F-FBnTP) to quantify the time-dependent apoptotic action of the taxanes paclitaxel and docetaxel in vitro and in vivo. Methods: The duration-dependent treatment effect of paclitaxel on 18F-FBnTP uptake was assayed in human MDA-MB-231 breast carcinoma cells. The expression of the proapoptotic Bax and antiapoptotic Bcl-2 mitochondrial proteins, release of the apoptogen cytochrome c, and activation of executioner caspase-3 were determined by Western blotting. The fraction of viable cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The effect of docetaxel on 18F-FBnTP and 18F-FDG uptake in orthotopic prostate tumors in mice was compared. Results: 18F-FBnTP cellular uptake in viable cells declined linearly with the increasing duration of paclitaxel treatment, from 3 to 24 h, and plateaued at 48 h. The extent of decrease of 18F-FBnTP correlated strongly with the Bax-to-Bcl-2 ratio (R2 = 0.83) and release of cytochrome c (R2 = 0.92), but preceded in time the caspase-3 cleavage. The P-glycoprotein blocker verapamil did not interfere with 18F-FBnTP cellular uptake. 18F-FBnTP prostate tumor contrast was greater than 18F-FDG prostate tumor contrast. Docetaxel caused a marked decrease (52.4%) of 18F-FBnTP tumor uptake, within 48 h, whereas 18F-FDG was much less affected (12%). Conclusion: The voltage sensor 18F-FBnTP is a viable means for quantification of paclitaxel pharmacodynamics. 18F-FBnTP permits the detection of paclitaxel apoptotic action in vivo earlier than does 18F-FDG. 18F-FBnTP may afford a novel approach for early detection and quantitative assessment of the cumulative-effect kinetics of proapoptotic drugs and conditions using PET.