Brian Austen, Yeser Mohammed and Elliott Cheng

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Presentation transcript:

Development of smart contrast agents for MRI imaging of Alzheimer’s Disease Brian Austen, Yeser Mohammed and Elliott Cheng BMS, St George’s University, Cranmer Terrace, LONDON SW17 ORE Imaging agents were synthesised by peptide synthesis, incorporating a protected DOTA residue at the final step for binding to gadolinium. After TFA deprotection and HPLC purification, Gd in 3 fold excess was incubated with the reagent, and the GD complex purified by HPLC. Reagents were characterised by maldi-mass spec R3 R2 R1 R1 +Gd R2 + Gd R3 + Gd Many (35%) MRI scans on patients are performed with the use of contrast agents which enhance selective tissues by increasing relaxation of adjacent water protons. Gd is the most common contrast agent, chosen as it contains 7 unpaired electrons which increase T1 longitudinal relaxation (protons realigning with the external field) and reduce T2 transverse relaxation (time for protons to exchange energy with other nuclei). Free Gd is toxic unless complexed with a stable ligand. The binding of reagents to Ab fibrils and oligomers was measured by ELISA, using the biotin moities incorporated into the reagents. R2 bound more strongly to fibrils than R1indicating that the hexa-DArg sequence applifies binding as well as acting as a cell penetration sequence That aggregation and deposition of 39-43-residue peptides, b-amyloid, in the brain of Alzheimer’s patients is associated with disease The aim is to develop imaging agents that contain gadolinium, bind b-amyloid plaques, and cross the blood-brain barrier. Imaging plaques in brain by MRI will provide an early diagnosis of Alzheimer’s, and permit monitoring of therapy designed to rid the brain of plaques. Amyloid-binding peptides were derived from retroinverted forms of the aggregation domain in bAmyloid NH2------VKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKK-------COOH NL GQ VI X Swedish double mutation 670/671 Flemish mutation 692 Florida 717 London mutations 716 Australian 723 b-Secretase a-Secretase g-Secretase Ab Extracellular domain Cytoplasmic tail APP K Italian Aggregation domain Retroinversion FFVLK N C -- Membrane FC2-1 100uM R1-R4 binding to amyloid 1-40 fibrils On a biacore, R2 and R3 bound more strongly to Ab fibrils than R1 or the control peptide R4. On and off rates were fast 40 42 G Dutch mutation 692 F DOTA- Gly-DArg-DPhe-DPhe-DVal-DLeu-DLys-Gly-DArg-Gly-Pentadiamine Gd b-Amyloid-binding Transport Contrast R1 Synthesised MRI contrast agents for imaging Alzheimer’s pathology DOTA –Gly-DArg-DPhe-DPhe-DVal-DLeu-DLys-DArg-rlsysrrrf-NH2 SynB b-Amyloid binding R3 R2 DOTA –Gly-DArg-DPhe-DPhe-DVal-DLeu-DLys-Gly-hexaDArg a-Synuclein binding R4 DOTA-Gly DArg-Vaa-Waa-Xaa-Yaa-Zaa-Gly-hexaDArg C D AD section plus R2 Young control plus R2 AD section plus antibody In AD pm sections, R2 stained plaques (A) and vascular amyloid (B), in a similar fashion to Ab antibodies (D). Sections froma control young patient did not bind R2 B A D C SW-APP 293 cells transfected with the amyloid precursor protein, treated with proteasome inhibitor, lactalysin,to accumulate Ab, took up and retained R2. Visulalised via incorporated biotin in R2 T2 image; plaques in CA3 of mouse hippocampus, not seen at 1hr MRI of APP/PS-1 double transgenic mouse 1 hr after in injection of R1 (0.5mg); thanks to Dr Mike Modo, Kings London