RT Journal Article
SR Electronic
T1 Human Brain Imaging and Radiation Dosimetry of <sup>11</sup>C-<em>N</em>-<em>Desmethyl</em>-Loperamide, a PET Radiotracer to Measure the Function of P-Glycoprotein
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 807
OP 813
DO 10.2967/jnumed.108.058453
VO 50
IS 5
A1 Nicholas Seneca
A1 Sami S. Zoghbi
A1 Jeih-San Liow
A1 William Kreisl
A1 Peter Herscovitch
A1 Kimberly Jenko
A1 Robert L. Gladding
A1 Andrew Taku
A1 Victor W. Pike
A1 Robert B. Innis
YR 2009
UL http://jnm.snmjournals.org/content/50/5/807.abstract
AB P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood–brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that 11C-dLop, compared with 11C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The purposes of this study were to determine whether 11C-dLop is a substrate for P-gp at the blood–brain barrier in humans and to measure the distribution of radioactivity in the entire body to estimate radiation exposure. Methods: Brain PET scans were acquired in 4 healthy subjects for 90 min and included concurrent measurements of the plasma concentration of unchanged radiotracer. Time–activity data from the whole brain were quantified using a 1-tissue-compartment model to estimate the rate of entry (K1) of radiotracer into the brain. Whole-body PET scans were acquired in 8 healthy subjects for 120 min. Results: For brain imaging, after the injection of 11C-dLop the concentration of radioactivity in the brain was low (standardized uptake value, ∼15%) and stable after approximately 20 min. In contrast, uptake of radioactivity in the pituitary was about 50-fold higher than that in the brain. The plasma concentration of 11C-dLop declined rapidly, but the percentage composition of plasma was unusually stable, with the parent radiotracer constituting 85% of total radioactivity after approximately 5 min. The rate of brain entry was low (K1 = 0.009 ± 0.002 mL·cm−3·min−1; n = 4). For whole-body imaging, as a measure of radiation exposure to the entire body the effective dose of 11C-dLop was 7.8 ± 0.6 μSv/MBq (n = 8). Conclusion: The low brain uptake of radioactivity is consistent with 11C-dLop being a substrate for P-gp in humans and confirms that this radiotracer generates negligible quantities of brain-penetrant radiometabolites. In addition, the low rate of K1 is consistent with P-gp rapidly effluxing substrates while they transit through the lipid bilayer. The radiation exposure of 11C-dLop is similar to that of many other 11C-radiotracers. Thus, 11C-dLop is a promising radiotracer to study the function of P-gp at the blood–brain barrier, at which impaired function would allow increased uptake into the brain.