Radioligand Applications in Translational Drug Development 

¹Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland 

Translational pharmacokinetic–pharmacodynamic (PK–PD) understanding hinges on establishing a mechanistic continuum from systemic exposure to target-site distribution, target engagement, biological response and, ultimately, disease-relevant effects. Notably, radioligand applications are uniquely positioned to quantitatively interrogate several of these otherwise difficult-to-access dimensions and therefore constitute powerful tools across translational drug development. 

Accelerator mass spectrometry (AMS) and molecular imaging modalities such as positron emission tomography (PET) provide complementary capabilities. AMS affords ultrasensitive quantification of 14C-labeled compounds and substrates in biological matrices, enabling human microtracer pharmacokinetics, mass-balance and metabolite investigations, as well as pathway-level interrogation of metabolic flux. PET, by contrast, enables non-invasive, quantitative and longitudinal assessment of tissue distribution, target expression and occupancy, organ kinetics, and downstream biological or disease biomarkers across preclinical species and humans. 

These capabilities can be organized within a five-pillar translational framework encompassing biodistribution, target occupancy, proximal pharmacodynamic effects, downstream biological activity and disease-relevant outcomes. Examples spanning central and peripheral target occupancy, tissue biodistribution, amyloid PET and isotope tracing of lipid metabolism illustrate how distinct radionuclide-enabled readouts can close critical gaps along the PK–PD continuum. Beyond classical PK–PD applications, dynamic imaging can further resolve organ-level disposition processes, including hepatic uptake and biliary clearance. 

Collectively, PET, AMS and related radioligand methodologies provide a quantitative toolbox to inform dose selection, test mechanistic hypotheses and reduce translational uncertainty from preclinical development through clinical proof-of-concept.