Dual Targeting Agents for Aβ Plaque/P-Glycoprotein and Aβ Plaque/Nicotinic Acetylcholine α4β2[asterisk] Receptors for Aβ Plaque Removal

• Published in: The Journal of nuclear medicine (1978) Vol. 59; p. 1630
• Main Authors: Samra, Gurleen, Dang, Kenneth, Ho, Heather, Baranwal, Aparna, Mukherjee, Jogeshwar
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.05.2018
• Subjects: Acetylcholine receptors (nicotinic); Affinity; Alzheimer's disease; Amyloid; Binding; Blood-brain barrier; Brain; Brain slice preparation; Cognitive ability; Cortex (frontal); Curcumin; Efflux; Feasibility studies; Ferulic acid; Fexofenadine; Glycoproteins; Medical treatment; Membrane permeability; Nervous system; Neurofibrillary tangles; P-Glycoprotein; Permeability; Proteins; Receptors; Reduction; Senile plaques; Substantia alba; Substantia grisea; Substrates; Thalamus
• ISSN: 0161-5505; 1535-5667

Objectives: Alzheimer’s disease (AD) affects 10% of people older than 65 and is characterized by a progressive loss of cognitive function with an abnormal accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain. Efforts to reduce brain Aβ plaques continue to be investigated as a therapeutic approach for AD. We report here development of dual targeting agents with affinity for Aβ plaque/P-glycoprotein (Pgp) or Aβ plaque/α4β2[asterisk] nicotinic acetylcholine receptors (nAChR). These novel dual agents may be able to efflux Aβ plaques when linked to Pgp substrate via the paravascular (glymphatic) pathways or increase their therapeutic efficacy by being anchored in the brain using the α4β2[asterisk] nAChR. Methods: Ferulic acid (FA), ferulic acid ethyl ester (FAEE) and curcumin (CUR) were used for Aβ plaques, fexofenadine (FEX) was used as substrate for Pgp and [18F]nifrolidine (NIF) was used for α4β2[asterisk] nAChRs in order to prepare the dual agents. Four dual agents, FA-FEX and CUR-FEX for Aβ/Pgp and FAEE-NIF and FA-NIF for Aβ/α4β2[asterisk] were synthesized. Binding affinity studies of Aβ plaque/α4β2[asterisk] nAChR were carried out in rat brain slices (10 μm) using 3H-cytisine for α4β2[asterisk] nAChR and [3H]PIB was used on post-mortem human AD frontal cortex sections (10 μm) for Aβ plaques. Results: Aβ plaque/α4β2[asterisk] nAChR dual agents, FAEE-NIF and FA-NIF exhibited IC50 =3 to 6 nM for α4β2[asterisk] nAChRs in thalamus and frontal cortex in rat brain slices. In postmortem human AD frontal cortex, Aβ plaques labeled with [3H]PIB, CUR-FEX showed a 35% reduction in grey matter (GM)/white matter (WM) [3H]PIB binding, while CUR alone showed a 50% reduction. Lower levels of [3H]PIB displacement were measured using FA, FA-NIF and FA-FEX. Conclusion: This initial feasibility study provides evidence about the potential suitability of the Aβ-Pgp and Aβ-α4β2[asterisk] nAChRs dual targeting for further evaluation as therapeutic and theranostic approaches for reducing brain Aβ plaques. Based on our previous findings with [18F]NIF, blood brain barrier (BBB) permeability for FA-NIF and FAEE-NIF is expected while permeability of CUR-FEX needs to be ascertained in ongoing studies.