Molecular Imaging News: PET Imaging and Neurodegenerative Diseases
By Heiko Kroth, PhD, and Julian JG Gray, MD, PhD
Vol. 24 No. 5 P. 26
Diagnosing neurodegenerative diseases is often challenging, especially in the early stages of the conditions. This is due to the chronic progression and accumulation of pathology many years ahead of clinical symptoms. Neuroimaging is playing an ever-increasing role in diagnosing these conditions.
However, while structural imaging of the brain using MRI is of great value, it cannot detect the underlying and early accumulating molecular changes of the conditions. Increased understanding of the biological basis of such conditions has led to the rapid development of biomarkers to measure the accumulation of abnormal proteins characteristic of these conditions. While fluid biomarkers in cerebrospinal fluid (CSF) and blood are quickly emerging, especially in Alzheimer’s disease (AD) and Parkinson’s disease (PD), imaging of the biological changes in the brain using PET or SPECT with radiotracers remains, for now, the gold standard. This is particularly true for PET imaging, which detects radioligands (tracers) spatially, allowing for quantification of pathological proteins in affected localized brain regions, something not possible using fluid biomarkers.
One of the first imaging successes was the development of the dopamine transporter scan (DaTSCAN), which uses the radionuclide I-123 to image dopamine transporters in presynaptic neurons using SPECT. Reduction of the expected uptake due to loss of presynaptic neurons in the substantia nigra and striatum may assist in the early diagnosis of PD. DaTSCAN imaging has proven useful in the often difficult differentiation of PD with predominant tremor from essential tremor. It can also assist in distinguishing Lewy body dementia from AD, as a reduced signal, similar to that observed in PD, is seen in the former but not the latter condition.
Getting closer to the molecular pathology itself, PET imaging using specific tracers is now able to quantitatively detect and localize early changes in levels of key proteins in the brain.
This approach is most advanced in AD, where the core pathological features, both senile plaques composed of amyloidbeta peptides and neurofibrillary tangles composed of hyperphosphorylated tubulin-associated unit (Tau) protein, can be imaged using PET ligands. Three fluorinated radioligands for imaging amyloid plaques have been approved: florbetapir (Amyvid), florbetaben (NeuraCeq), and flutemetamol (Vizamyl). Such agents add value in the early detection of amyloid pathology in subjects with mild cognitive impairment, where differentiation from depression and other causes of cognitive impairment can be very difficult. Up to one-third of subjects screened for inclusion into studies of early symptomatic AD are found to lack amyloid pathology, ie, do not have AD. Moving to earlier, asymptomatic populations, the proportion of amyloidnegative cases is generally higher. Measurement of amyloid-beta in CSF (where levels are reduced) also plays a role and can better detect changes in toxic amyloid species such as oligomers, but sampling CSF is more invasive and potentially risky; more sensitive bloodb ased assays are also rapidly gaining ground, but direct measurement using PET remains a powerful tool for both diagnosis and tracking changes over time.
Demonstration of a marked reduction in amyloid plaques played a key role in the accelerated approval of monoclonal antibodies such as aducanumab and lecanemab which clear plaques from the brain, making this a useful biomarker for drug development. With the FDA recently accepting amyloid PET as a surrogate marker for clinical trials in AD, the technique has evolved into a critically important tool in drug development. The technique also allows the inclusion of subjects at risk of AD for prevention studies, such as in adults with Down syndrome, as in our ongoing study of ACI-24, a vaccine targeting amyloid-beta.
New Research Targets
Radioligands imaging neurofibrillary tangles consisting of abnormally phosphorylated Tau species are also under intensive development, with one such agent—flortaucipir (Tauvid)—already approved in the United States. The Tau PET tracer PI-2620—developed in collaboration with Life Molecular Imaging—has shown high selectivity for pathological Tau species. It is currently in a Phase 3 study that will enroll around 200 subjects with advanced AD, with imaging findings to be correlated with pathology at postmortem, a challenging but necessary step in the development of tracers in the neurodegenerative field. A particular feature of PI-2620 is its strong binding to so-called 4-R Tau, an isoform with four microtubule-binding repeats. This makes it potentially valuable in the diagnosis of so-called 4-R tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration.
PSP is a condition that is notoriously difficult to diagnose in its early stages, with differentiation from atypical PD being a particular challenge. In a recent study published in the Journal of Nuclear Medicine, the sensitivity and specificity for discrimination of PSP from healthy controls were increased from 83% and 90% to 94% and 100%, respectively, when imaging with the Tau-PET ligand PI-2620 combined with structural MRI, compared with MRI imaging alone. The increased sensitivity was especially high for subjects with less pronounced clinical symptoms or signs.
Alpha-synuclein has proven to be a difficult target for PET ligand development. Such a ligand will be important for the imaging of aggregated alpha-synuclein and the early diagnosis of PD and other alpha-synucleinopathies such as Lewy body dementia and multisystem atrophy. The latter presents another diagnostic challenge in its early stages, and it is exciting that imaging with the alpha-synuclein PET tracer ACI-12589 recently allowed in vivo demonstration of alpha-synuclein aggregates in the brains of patients with multisystem atrophy for the first time.
At the heart of the development of tracers is the discovery and development of molecules with suitable properties to selectively target the protein of interest. The molecule must not only bind with high affinity and selectivity to the target protein but also possess favorable pharmacokinetic properties. For the many protein targets which are predominantly present intracellularly, the optimal molecule must also be able to penetrate the cell membrane.
At AC Immune, the Morphomer platform of brain-permeable small molecules has allowed the discovery and development of novel PET tracers with high affinity and selectivity to detect pathologic Tau, alpha-synuclein, and transactive response DNA binding protein (TDP-43) aggregates in humans. This was achieved using a rational chemical design strategy supported by iterative cycles of in vitro aggregate binding and optimization of the physicochemical properties of the small molecules. Compound selection requires favorable pharmacokinetic properties (fast brain uptake followed by complete washout of any unbound activity), lack of defluorination, lack of potentially image-confounding metabolites, and substitution patterns which support a straightforward introduction of the radioactive label by routine synthesis methods.
Important elements of the Morphomer platform are built-in structural features favoring brain penetration and cell uptake, ie, conformation-specific, nondye, and nonpeptidic small molecules designed for targeting intracellular aggregates.
Looking to the future, one of the next targets of interest is TDP-43. Aggregates of this protein occur in motor neurons in amyotrophic lateral sclerosis and in the frontal and temporal lobes in patients with frontotemporal lobar degeneration. Since the pathology in frontotemporal lobar degeneration is mixed, with some patients having predominant Tau rather than TDP-43 pathology, imaging of the molecular targets will help not only in diagnosis but also in selecting patients for treatments targeting the appropriate pathology.
In conclusion, it is clear that neuroimaging with increasingly specific PET tracers will be an important component of a precision medicine approach to early diagnosis and treatment of these devastating conditions.
— Heiko Kroth, PhD, is a chemistry group expert for AC Immune SA. He has more than 20 years of experience in the pharmaceutical industry as a medicinal chemist. In his current role, he leads the SME discovery and compound management group at AC Immune in Lausanne, Switzerland.
— Julian JG Gray, MD, PhD, has served as clinical advisor to AC Immune SA’s programs in neurodegenerative diseases since January 2007 and works in this function exclusively for AC Immune. He has previously held the position of head of central nervous system (CNS) therapeutics at Eisai Ltd in London, leading the global development of early- and late-stage CNS projects in Alzheimer’s disease, Parkinson’s disease, and other CNS areas.