In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after median disease duration of 4.7 years (0.5-12.4 years). (18)F-AV-1451 positron emission tomography may be the first radiotracer to reflect the loss of pigmented neurons in the substantia nigra of parkinsonian patients. The magnitude of the nigral signal loss was smaller than the decrease in striatal dopamine transporter signal measured by dopamine transporter single photon emission computed tomography. These findings suggest a more severe loss of striatal nerve terminal function compared with neuronal cell bodies, in accordance with the post-mortem literature

[11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

Purpose Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases. Methods Specificity and selectivity of [3H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM). Results [3H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (Kd = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (Kd = 19 ± 6.4 nM) as well as amyloid-β1–42 fibrils (Kd = 20 ± 10 nM). [11C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d3)-[11C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein. Conclusion MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties