PET in neurotherapeutic discovery and development

Abstract

Positron emission tomography (PET) is a highly sensitive, quantitative imaging technique that can track sub-nanomolar quantities of positron-emitting radionuclides throughout the body. By incorporating such radionuclides into molecules of interest, we can directly assess their pharmacokinetic and pharmacodynamic (PK/PD) characteristics in vivo without changing their physicochemical characteristics or eliciting a pharmacological response. As such, PET imaging has long been used as a tool to aid drug discovery programs from preclinical biomarker validation all the way through to clinical trials. In this perspective we discuss the use of PET radioligands in central nervous system (CNS) drug discovery and development, with a focus on recent applications in psychiatry (e.g. 5-HT₂A, 11β-HSD1), neuro-oncology (e.g. KRAS^G12C, ATM, ALK2), and neurodegeneration (e.g. amyloid beta plaques, MAPK p38), while exploring the intricacies associated with developing novel radiotracers for CNS targets. Examples highlight the preclinical and clinical uses of PET for studying biomarker function, drug candidate PK/PD, target occupancy/engagement, dosing regimen determination, clinical trial patient selection, and quantifying biomarker changes in response to treatments.

Keywords: Carbon-11; Fluorine-18; Neuroimaging; Positron emission tomography; Radiochemistry; Small molecule drug development.

Fig. 1

Graphic depicting the drug discovery process, in which millions of chemical structures are eventually narrowed down to one approved drug – a costly and time-consuming process. The numerous ways in which molecular imaging can be applied to aid attrition rates and inform drug development at various stages are shown.

Fig. 2

(A) Structure of [¹¹C]Cimbi-36. (B) Relationship between subjective intensity rating after psylocibin dosing and neocortical 5-HT₂AR occupancy. (C) Relationship between subjective intensity rating and plasma psilocin concentration. Adapted from Madsen MK et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacol 2019; 44:1328–1334. Springer Nature.

Fig. 3

Structures of 11β-HSD1 radiotracers (A) [¹¹C]AS2471907 and (B) [¹⁸F]AS2471907. (C) Participant's MRI and co-registered parametric [¹⁸F]AS2471907 V_T images in age-matched and sex-matched individuals with alcohol-use disorder (AUD) versus healthy control (HC). Adapted from Verplaetse TL et al. Imaging a putative marker of brain cortisol regulation in alcohol use disorder. Neurobiol Stress 2024; 29:100609. Copyright (2024), with permission from Elsevier.

Fig. 4

(A) Structure of radiolabeled [¹¹C]AZD4747. (B) [¹¹C]AZD4747 PET images (average SUV 5–123 ​min) in two cynomolgus monkeys. Adapted with permission from Kettle, J.G. et al. Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration. J Med Chem 2023; 66(13):9147–9160. Copyright 2023 American Chemical Society.

Fig. 5

Structures of (A) [¹¹C]AZD0156 ([¹¹C]4), (B) [¹¹C]21, and (C) [¹¹C]AZD1390 ([¹¹C]24) with their respective summed 5–123 ​min PET images in NHPs. Adapted with permission from Pike KG et al. Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood–Brain Barrier: The Discovery of AZD1390. J Med Chem 2024; 66(13):9147–9160. Copyright 2024 American Chemical Society.

Fig. 6

(A) Structure of [¹¹C]M4K2127. (B) [¹¹C]M4K2127 PET images (average SUV 0–90 ​min) in a healthy rodent. Adapted with permission from Chassé M et al. Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of ¹¹C-Labeled ALK2 Inhibitors. ACS Med Chem Lett 2021; 12:846–850. Copyright 2021 American Chemical Society.

Fig. 7

(A) Structure of [¹¹C]talmapimod. (B) [¹¹C]Talmapimod PET images (average SUV 0–90 ​min) in healthy rodent at baseline and after P-glycoprotein drug efflux transporter inhibition with 5 ​mg/kg elacridar administered 30 ​min prior to radiotracer injection. Adapted with permission from Chassé M et al. In vitro and in vivo evaluation of [¹¹C]M4K2127 for PET imaging activin receptor-like kinase 2. Nucl Med Biol 2023; 126: 108677.

Fig. 8

(A) Change in the score on the Clinical Dementia Rating (CDR)–Sum of Boxes (CDR-SB) from baseline in an 18-month, multicenter, double-blind, phase 3 trial of lecanemab in patients with early AD versus placebo group. (B) Adjusted mean change in amyloid burden in treatment versus placebo groups as measured by amyloid PET using (C) [¹⁸F]florbetapir (Amyvid®), (D) [¹⁸F]florbetaben (Neuraceq®), or (E) [¹⁸F]flutemetamol (Vizamyl®). Graphical data adapted with permission from van Dyck et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023; 388:9–21.

Fig. 9

(A) Structure of [¹⁸F]Flortaucipir (Tauvid™, [¹⁸F]AV-1451, [¹⁸F]T807). (B) Structure of [¹⁸F]OXD-2314.