Neuroimaging of Alzheimer´s disease (AD) with Positron Emission Tomography (PET)

PET is a well-established neuroimaging method in identifying AD. An ideal PET biomarker for AD should allow a reliable estimation of disease risk and rate of disease progression long before first symptoms are clinically diagnosed. The main pathologic processes of AD, deposition of β-amyloid, hyperphosphorylated tau protein, degeneration of cholinergic and other neurons, precede clinical symptoms by years providing potential targets for the identification of individuals at risk for AD.
In the last few years, several PET tracers targeting β-amyloid in AD have been developed, such as [¹¹C]PIB, [¹⁸F]florbetaben, [¹⁸F]florbetapir, [¹⁸F]flutemetamol. The suitability of these PET radiopharmaceuticals to differentiate AD patients and patients with mild cognitive impairment (MCI) from control subjects has been demonstrated. However β-amyloid deposition has been found in about 20% of normal elderly subjects. Therefore other potential neuroimaging biomarkers, for instance based on radiopharmaceuticals for the cholinergic system may be of interest.
Loss of nicotinic acetylcholine receptors (nAChRs) is a major contributor to the cognitive deterioration in AD. The α4β2-nAChR subtype is thought to be the most severely reduced in the onset of AD. Using 2-[¹⁸F]F-A85380 PET we showed a significant decline in α4β2-nAChRs in early AD which correlated significantly with the loss of cognitive function. Because this tracer is not suitable as a biomarker in a routine clinical set-up for early AD-diagnosis we developed the new radiotracer (-)-[-[¹⁸F]flubatine with faster kinetics, significantly improved brain uptake and better image quality.
Our further attempts for development of PET biomarkers include the α7nAChR and σ₁ receptors as targets, as both are suggested to be involved in early AD. [¹⁸F]NS10743 and [¹¹C]NS14492 are radioligands which show high brain uptake, regional distribution and dose-dependent blockade in accordance with α7nAChR expression pattern in animal PET studies and are promising for in vivo mapping and quantitative imaging of α7nAChR in AD. For PET imaging of σ₁ receptors a series of fluoroalkyl substituted spirocyclic piperidines was developed and (S)-[-[¹⁸F]fluspidine has been selected as the most promising for molecular imaging in human.
Taken together, there is optimism that it might be possible in future to improve early neuroimaging diagnosis of AD as a multifactorial disorder by a multi-tracer PET imaging strategy, with important implications for early preventive/therapeutic interventions.