Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 2

PET Biomarkers for Inflammation and the P-gp Efflux Transporter: Translation of Imaging from Animals to Humans

Robert B. Innis, M.D., Ph.D.
National Institute of Mental Health, NIH

I will discuss two recently developed radioligands that may be useful in vivo biomarkers: one for inflammation and the other for an efflux transporter (P-gp) that is widely distributed in the body.

Inflammation. The peripheral benzodiazepine receptor (PBR and also called translocator protein (18 kDa)) was initially characterized as a high affinity binding site for diazepam displaceable with Ro5-4864 (4'-chloro-diazepam) and is present at high densities in lung, liver, heart, spleen, and kidney. PBRs are transmembrane proteins located primarily in mitochondria and may play important roles in cholesterol transport, hormone synthesis, and immunomodulation. PBRs have lower concentrations in healthy brain than in peripheral organs and are primarily located in glial cells, with highest densities in olfactory bulb, choroid plexus, and the ependymal lining of the ventricles. PBR expression is markedly increased in activated microglia and reactive astrocytes in the central nervous system and may be a useful biomarker of neuroinflammation. For example, we imaged and quantified increased densities of PBRs surrounding a cerebral stroke in rats with positron emission tomography (PET). I will describe our studies with one particular radioligand, [¹¹C]PBR28, in rats, monkeys, and humans.

P-gp Efflux Transporter. The Permeability-glycoprotein (P-gp) efflux pump prevents brain uptake of pharmaceuticals and radiopharmaceuticals from several chemical classes but shows preference for ampipathic molecules that have both a lipophilic and a positively charged domain. P-gp is a can transport substances while in the lipid bilayer – namely, before they actually cross the membrane. The physiological function of P-gp is presumed to be protection of several tissues, including brain, cerebral spinal fluid, and testes, from endogenous toxins or xenobiotics in blood. P-gp is a member of the large family of ATP-binding cassette (ABC) transporters and is designated ABCB1. A second member, XX Is it ABCC1 or ABCG1, also exists at and is part of the blood-brain barrier. Finally, over expression of P-gp in cancer cells may be responsible for 25% of human cases of multidrug resistance by preventing entry of chemotherapeutic agents. Loperamide, an opiate receptor agonist, does not cross the blood-brain barrier because it is a substrate for the Permeability-glycoprotein (P-gp) efflux pump. We evaluated [¹¹C]loperamide as a positron emission tomography (PET) radioligand to measure brain P-gp function in vivo.

Up to Top