Engineered antibodies: new possibilities for brain PET?

International audienceAlmost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands

PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome.

Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourette's syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourette's syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourette's syndrome. Mean caudate and putamen 18F-dopa influx constants were similar in patients with Tourette's syndrome and controls, and there was no difference in striatal 18F-dopa uptake between the treated and untreated Tourette's syndrome groups. Mean caudate and putamen 11C-raclopride binding potentials in patients with Tourette's syndrome were also similar to control values. The findings suggest that striatal metabolism of exogenous levodopa and the density of striatal D2 receptors are both normal in patients with Tourette's syndrome and that Tourette's syndrome does not arise from a primary dysfunction of dopaminergic terminals

Quantification of subendocardial and subepicardial blood flow using 15O-labeled water and PET: Experimental validation

The purpose of this study was to assess the feasibility and accuracy of quantifying subendocardial and subepicardial myocardial blood flow (MBF) and the relative coronary flow reserves (CFR) using 15O-labeled water (H2 15O) and 3-dimensional-only PET. Methods: Eight pigs were scanned with H215O and 15O-labeled carbon monoxide (C15O) after partially occluding the circumflex (n = 3) or the left anterior descending (n = 5) coronary artery, both at rest and during hyperemia induced by intravenous dipyridamole. Radioactive microspheres were injected during each of the H215O scans. Results: In a total of 256 paired measurements of MBF, ranging from 0.30 to 4.46 mL·g-1·min-1, microsphere and PET MBF were fairly well correlated. The mean difference between the 2 methods was -0.01 ± 0.52 mL·g-1·min-1 with 95% of the differences lying between the limits of agreement of -1.02 and 1.01 mL·g-1·min-1. CFR was significantly reduced (P < 0.05) in the ischemic subendocardium (PET = 1.12 ± 0.45; microspheres 5 1.09 ± 0.50; P = 0.86) and subepicardium (PET = 1.2 ± 0.35; microspheres = 1.32 ± 0.5; P = 0.39) in comparison with remote subendocardium (PET = 1.7 ± 0.62; microspheres 5 1.64 6 0.61; P 5 0.68) and subepicardium (PET = 1.79 ± 0.73; microspheres = 2.19 ± 0.86; P = 0.06). Conclusion: Dynamic measurements using H2 15O and a 3-dimensional-only PET tomograph allow regional estimates of the transmural distribution of MBF over a wide flow range, although transmural flow differences were underestimated because of the partial-volume effect. PET subendocardial and subepicardial CFR were in good agreement with the microsphere values