A clear picture of a drug’s action within the brain
Positron emission tomography (PET) provides researchers the ability to perform ‘precision’ pharmacology by combining the measurement of a variety of biological processes involving receptors, enzymes, and transporters with the measurement of the biodistribution of a labelled drug. PET can be used to answer key questions in drug development by providing information regarding successful target binding based on measurable changes in protein density, receptor occupancy, glucose metabolism and perfusion, oxygen utilisation, and/or blood-brain barrier integrity. At CHDR, we can also combine quantitative PET imaging with intensive pharmacokinetics sampling, pharmacodynamics tests such as NeuroCart® and PainCart®, and ‘wet’ biomarkers, to obtain even more information about a drug.
Collaboration with the VU University Medical Center (VUmc)
Because pharmacological applications for PET are based on the availability of specific probes at the imaging centre, CHDR collaborates with one of the largest PET facilities in the world — the VU University Medical Center (VUmc) in Amsterdam — to conduct a wide range of cutting-edge PET studies. VUmc has a dedicated radiochemistry facility for producing a wide range of radiotracers in accordance with GMP regulations. In addition, CHDR has a Clinical Research Unit at VUmc, which provides sponsors with state-of-the-art clinical imaging services for use in early clinical drug development.
− PET imaging provides unique insights into the interaction between a test compound and specific molecules in the body, helping bridge preclinical and early clinical drug development.
− The Clinical Research Unit can perform functional CNS and electrophysiology testing both before and after PET imaging.
− The VUmc PET imaging centre has more than two decades of experience using PET data to model tracer kinetics.
− Our expertise with PK/PD modelling allows us to study the relationship between plasma drug levels and drug binding in the target tissue.
− Our ability to visualise and quantify immune reactions using PET has led to the development of new antibody-based drugs in a variety of clinical fields, including oncology.
Practical answers to important research questions
Does our test compound pass the blood-brain barrier and bind its target?
Studying the biodistribution of a drug labelled with a positron-emitting radioisotope can reveal the drug’s ADME (administration, distribution, metabolism, and elimination) profile. In addition, using a labelled tracer that binds specifically to the drug’s target can help confirm the interaction between the study drug and its target by showing changes in radiotracer binding; this approach is similar to competitive antagonism.
How can we determine the optimal dose of our test drug?
Using PET imaging, researchers can estimate the optimal dose of a test compound for further clinical development. For example, CHDR recently studied a novel, low-affinity dopamine D2 receptor antagonist that was being developed as an antipsychotic drug. Healthy subjects were given a fixed dose of 11C-labelled raclopride, a synthetic D2 receptor antagonist, followed by various oral doses of the test compound. The relationship between the dose of the test drug and [11C]raclopride binding — combined with plasma levels of the test dose — allowed our researchers to determine the drug’s safety, tolerability, and CNS pharmacodynamics, thereby providing key information regarding the optimal dose for use in clinical development.
What is the relationship between the dose of the drug, receptor occupancy, and pharmacological effects?
CHDR has extensive experience developing and performing functional testing, particularly in the CNS. For example, both NeuroCart® and PainCart ® can be used to measure a drug’s effects on a variety of neurophysiological parameters, including attention, memory, and psychomotor performance. Researchers at CHDR recently combined PET imaging with NeuroCart ® to show that increased levels of dopamine in the brain following amphetamine administration are correlated with improved impulse control. With respect to new compounds, a wealth of information for use in future studies can be obtained using analytical models to correlate dose, blood concentration, functional effects, and receptor occupancy.