PET in drug biodistribution studies

In the early phase of development of a new drug, PET can be used to non-invasively determine the in vivo biodistribution of the drug molecule to study whether it reaches the target tissue in sufficient amounts, and does not accumulate in toxic amounts in other tissues. Any organic molecule can be labelled with positron-emitting isotope, without changing its chemical structure or properties. Due to the high sensitivity of PET, the administered drug doses for biodistribution studies can be kept so small that toxic effects are impossible. This PET-microdosing concept (Bergström et al., 2003) reduces the need for preclinical safety testing. In the next stages, higher and even therapeutic drug mass is useful for assessing the dose linearity (Wagner & Langer, 2011) and suitable drug dosage.

In PET biodistribution study the concentration-time course of the isotope label, used to label the drug molecule, is easy to measure in the tissue of interest. If the course of concentration in blood plasma is simultaneously assessed, then it is possible to apply kinetic compartmental models to estimate plasma-to-tissue clearance and distribution volume (equilibrium tissue-to-plasma ratio) of the drug. Often the measured total radioactivity concentration in plasma and tissue consists of both the authentic labelled drug and its label-carrying metabolites; the plasma curve must then be corrected for metabolites, while the contribution of label-carrying metabolites to the tissue curves could be taken into account in the kinetic models.

In central nervous system, the blood-brain barrier forms the first obstacle to many drug candidates, letting through mainly small-molecular weight lipophilic compounds. In other tissues the permeability of endothelial barrier is less limiting, and very permeable in the spleen, liver, and bone marrow. Endothelial cells express a wide array of transporters and receptors, which can carry therapeutic drugs and radiopharmaceuticals across the barrier. ATP-dependent export proteins, mainly P-glycoprotein (P-gp, ABCB1) transports diverse substrates from CNS to the capillaries, effectively minimizing the biodistribution of many drug candidates in the brain. Cancer can develop multidrug resistance by up-regulation of transporters that remove anticancer drugs from the cancer cells (Pérez-Tomás, 2006). Concomitant administration of multiple drugs that are recognized by the same transporters may lead to changes in pharmacokinetics and side effects or loss of efficacy. This transporter-mediated drug-drug interaction (DDI) can be studied with PET, using labelled drug with and without transporter inhibitor (Langer, 2016; Tournier et al., 2018).

See also:


Bergström M, Långström B. Pharmacokinetic studies with PET. Progr Drug Res. 2005; 62: 280-317. doi: 10.1007/3-7643-7426-8_8.

Fischman AJ, Alpert NM, Rubin RH. Pharmacokinetic imaging - a noninvasive method for determining drug distribution and action. Clin Pharmacokinet. 2002; 41(8): 581-602. doi: 10.2165/00003088-200241080-00003.

Gunn RN, Rabiner EA. Imaging in central nervous system drug discovery. Semin Nucl Med. 2017; 47(1): 89-98. doi: 10.1053/j.semnuclmed.2016.09.001.

Matthews PM, Rabiner EA, Passchier J, Gunn RN. Positron emission tomography molecular imaging for drug development. Br J Clin Pharmacol. 2012; 73(2): 175-186. doi: 10.1111/j.1365-2125.2011.04085.x.

Wagner CC, Langer O. Approaches using molecular imaging technology - use of PET in clinical microdose studies. Adv Drug Deliv Rev. 2011; 63(7): 539-546. doi: 10.1016/j.addr.2010.09.011.

Wong DF, Tauscher J, Gründer G. The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacology 2009; 34(1): 187-203. doi: 10.1038/npp.2008.166.

Tags: ,

Updated at: 2021-02-19
Created at: 2021-02-18
Written by: Vesa Oikonen