PET as a Translational Tool in Drug Development for Neuroscience Compounds

Abstract

In central nervous system drug discovery programs, early development of new chemical entities (NCEs) requires a multidisciplinary strategy and a translational approach to obtain proof of distribution, proof of occupancy, and proof of function in specific brain circuits. Positron emission tomography (PET) provides a way to assess in vivo the brain distribution of NCEs and their binding to the target of interest, provided that radiolabeling of the NCE is possible or that a suitable radioligand is available. PET is therefore a key tool for early phases of drug discovery programs. This review will summarize the main applications of PET in early drug development and discuss the usefulness of PET microdosing studies performed with direct labelling of the NCE and PET occupancy studies. The purpose of this review is also to propose an alignment of the nomenclatures used by drug metabolism and pharmacokinetic scientists and PET imaging scientists to indicate key pharmacokinetic parameters and to provide guidance in the performance and interpretation of PET studies. CONCEPT OF MICRODOSING STUDIES BY RADIOLABELING OF DRUG MOLECULESBrain exposure and distribution of an NCE can be evaluated with direct radiolabeling of the compound with a short-lived

Development of 18F-Labeled PET Tracer Candidates for Imaging of the Abelson Non-receptor Tyrosine Kinase in Parkinson’s Disease

“…As mentioned above, this was a pilot study with n = 1 for the brain, which makes it difficult to draw conclusions. There are no thresholds for K p,uu ratios reported for PET tracers, but general thresholds for CNS drugs have been proposed . For example, a compound with a K p between 0.3 and 0.5 should have sufficient access to cross the blood–brain barrier (BBB) .…”

“…Only 7 of these drugs had a rat K p,uu below 0.3 . Undoubtedly, strict thresholds for advancing a compound may be difficult to establish since this will depend on the specific project, i.e., target expression, disease and developed compounds . Second, species’ differences in brain penetrations should be taken into account, especially concerning efflux transporter liability .…”

“…There are no thresholds for K p,uu ratios reported for PET tracers, but general thresholds for CNS drugs have been proposed. 31 For example, a compound with a K p between 0.3 and 0.5 should have sufficient access to cross the blood− The concentration of test compound in the selectivity screening was as follows: 1 μM for 2, 480 nM for 3 and 448 nM for 4. The concentration of test compound was 100-fold of the previously determined IC 50 for c-Abl.…”

“…33 Undoubtedly, strict thresholds for advancing a compound may be difficult to establish since this will depend on the specific project, i.e., target expression, disease and developed compounds. 31 Second, species' differences in brain penetrations should be taken into account, especially concerning efflux transporter liability. 34 With regard to c-Abl, the expression levels of this kinase are reported to be low and without regional differences in normal brain for both mice and humans.…”

Pharmacokinetic Study of Intranasal Dexamethasone and Methylprednisolone Compared with Intravenous Administration: Two Open-Label, Single-Dose, Two-Period, Two-Sequence, Cross-Over Study in Healthy Volunteers

“…However, to extend the use of this pathway for the control of systemic and central inflammation that accompanies different pathologies in patients, the results of CNS bioavailability studies supporting its use are required. In this context, future studies of pharmacokinetics in the CNS of GC in healthy brains may be performed by positron emission tomography while employing the adequate radiolabeled tracers [ 61 ].…”