Phosphodiesterase 10A PET radioligand development program: from pig to human

Area of Science:

• Radiochemistry and Nuclear Medicine
• Neuroscience
• Pharmacology

Background:

• Phosphodiesterase 10A (PDE10A) is a key enzyme in the brain implicated in various neurological disorders.
• Developing selective and effective PET tracers is crucial for visualizing and quantifying PDE10A in vivo.
• Existing tracers like (11)C-MP-10 provide a benchmark for evaluating novel radioligands.

Purpose of the Study:

• To synthesize and characterize novel PET tracers for PDE10A.
• To compare the performance of new tracers against the established (11)C-MP-10 in preclinical models.
• To identify the most promising candidate for human evaluation.

Main Methods:

• Four novel PDE10A PET tracer candidates (IMA102, IMA104, IMA107, IMA106) were synthesized and radiolabeled with (11)C or (18)F.
• In vitro characterization and pilot in vivo PET studies were conducted in pig brains.
• Promising candidates, (11)C-IMA107 and (11)C-IMA106, were further evaluated in primate brains alongside (11)C-MP-10.
• Pharmacological blockade studies with selective PDE10A inhibitors were performed.

Main Results:

• All synthesized tracers exhibited good radiochemical yields and specific activity, readily crossing the blood-brain barrier.
• (11)C-IMA107 and (11)C-MP-10 demonstrated favorable tissue kinetics and heterogeneous brain distribution mirroring PDE10A expression.
• In vivo studies confirmed dose-dependent reduction in tracer binding upon administration of PDE10A inhibitors.
• (11)C-IMA107 showed reversible kinetics and was well-described by a two-tissue compartment model in primates.

Conclusions:

• (11)C-IMA107 emerged as the leading PET tracer, offering high binding potential and reversible kinetics.
• First-in-human studies confirmed the expected biodistribution and suitable kinetics of (11)C-IMA107.
• (11)C-IMA107 is poised to be a valuable tool for investigating PDE10A status in the living human brain.