NIMH DIRP Molecular Imaging Branch - Section on PET Imaging

Background. Permeability glycoprotein (P-gp) is an efflux transporter that protects the body from many exogenous toxins but also blocks entry into cells of many therapeutic drugs. For example, P-gp is part of the blood-brain barrier as well as the blood-testis barrier and blocks entry of some toxins and drugs into these two organs.

Loperamide (Imodium ®) is a potent opiate agonist and an over-the-counter anti-diarrheal drug. Loperamide acts via opiate receptors in gut to slow motility but has no effects on the central nervous system, because P-gp avidly blocks its entry into the brain.

P-gp is also expressed in many organs of the body and significantly modulates the distribution, metabolism, and excretion of drugs. P-gp also plays a role in pathophysiology. Many tumors become resistant to cancer chemotherapies, and P-gp is over-expressed in a high percentage of these multi-drug resistant tumors. P-gp blocks the entry of cancer chemotherapies into the cell, thereby blocking their therapeutic effects.

Legend. We injected a radiolabeled analog of loperamide into a healthy male subject and scanned the body for about two hours. The compound was the 11C–labeled metabolite of loperamide – namely, desmethyl–loperamide. P–gp is working properly in this subject, since we see no radioactivity in brain or testes. Download the movie clip that shows a 3D rotating image acquired in the first few minutes after injection of radioligand. The rotating image shows the venous sinuses surrounding the brain. P–gp excludes the radioligand from both brain and cerebrospinal fluid. In fact, P–gp is so efficient that we can see the higher concentration of radioligand in the venous drainage from brain and cerebrospinal fluid.

References.
J.-S. Liow, W. Kreisl, S.S. Zoghbi, N. Lazarova, N. Seneca, R.L. Gladding, A. Taku, P. Herscovitch, V.W. Pike, and R.B. Innis. P-glycoprotein function at the blood-brain barrier imaged using ¹¹C-N-desmethyl-loperamide in monkeys. J. Nucl. Med., 50: 108-115, 2009. (PDF File)

N. Seneca, S. Zoghbi, J.-S. Liow, W. Kreisl, P. Herscovitch, K. Jenko, R.L. Gladding, A. Taku, V.W. Pike, and R. B. Innis. Human Brain Imaging and Radiation Dosimetry of ¹¹C-N-desmethylloperamide, a Positron Emission Tomographic Radiotracer to Measure the Function of P-glycoprotein, J. Nucl. Med, 50: 807-813, 2009 (PDF File)

W.C. Kreisl, J.-S. Liow, N. Kimura, N. Seneca, S.S. Zoghbi, P. Herscovitch, V.W. Pike, and R.B. Innis. P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer ¹¹C-N-desmethyl-loperamide. J. Nucl. Med., 51: 559-566, 2010. (PDF File)

Download Rotating Subject (.AVI) (16.5 Mb)