Neutral Ligands as Potential 64Cu Chelators for Positron Emission Tomography Imaging Applications in Alzheimer's Disease.

Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer's disease (AD). The development of longer-lived radiolabeled compounds is essential for further expansion of the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as 64Cu (t1/2 = 12.7 h, ß+ = 17%, ß- = 39%, electron capture EC = 43%, and Emax = 0.656 MeV) can accomplish this task. One limitation of 64Cu PET agents for neuroimaging applications is their limited lipophilicity due to the presence of several anionic groups needed to ensure strong Cu chelation. Herein, we evaluate a series of neutral chelators containing the 1,4,7-triazacyclononane or 2,11-diaza[3.3](2,6)pyridinophane macrocycles that have pyridyl-containing arms incorporating Aß-peptide-interacting fragments. The crystal structures of the corresponding Cu complexes confirm that the pyridyl N atoms are involved in binding to Cu. Radiolabeling and autoradiography studies show that the compounds efficiently chelate 64Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections versus wild-type controls.

Amyloid ß-Binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu Positron Emission Tomography Imaging in Alzheimer's Disease.

Herein, we report a new series of bifunctional chelators (BFCs) with a high affinity for amyloid aggregates, a strong binding affinity toward Cu(II), and favorable lipophilicity for potential blood-brain barrier penetration. The alkyl carboxylate ester pendant arms offer up to 3 orders of magnitude higher binding affinity toward Cu(II) and enable the BFCs to form stable 64Cu-radiolabeled complexes. Among the five compounds tested, the 64Cu-YW-7 and 64Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these BFCs have promising partition coefficient (log Doct) values of 0.91-1.26 and show some brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography imaging agents for AD diagnosis.

Reactions of propargyl compounds containing a cyclobutyl group induced by a ruthenium complex.

Reactions of [Ru]Cl ([Ru] = {Cp(PPh(3))(2)Ru}; Cp = cyclopentadienyl) with three alkynyl compounds, 1, 5, and 8, each containing a cyclobutyl group, are explored. For 1, the reaction gives the vinylidene complex 2, with a cyclobutylidene group, through dehydration at C(δ)H and C(γ)OH. With an additional methylene group, compound 5 reacts with [Ru]Cl to afford the cyclic oxacarbene complex 6. The reaction proceeds via a vinylidene intermediate followed by an intramolecular cyclization reaction through nucleophilic addition of the hydroxy group onto C(α) of the vinylidene ligand. Deprotonation of 2 with NaOMe produces the acetylide complex 3 and alkylations of 3 by allyl iodide, methyl iodide, and ethyl iodoacetate generate 4 a-c, respectively, each with a stable cyclobutyl group. Dehydration of 1 is catalyzed by the cationic ruthenium acetonitrile complex at 70 °C to form the 1,3-enyne 7. The epoxidation reaction of the double bond of 7 yields oxirane 8. Ring expansion of the cyclobutyl group of 8 is readily induced by the acidic salt NH(4)PF(6) to afford the 2-ethynyl-substituted cyclopentanone 9. The same ring expansion is also seen in the reaction of [Ru]Cl with 8 in CH(2)Cl(2), affording the vinylidene complex 10, which can also be obtained from 9 and [Ru]Cl. However, in MeOH, the same reaction of [Ru]Cl with 8 affords the bicyclic oxacarbene complex 12 a through an additional cyclization reaction. Transformation of 10 into 12 a is readily achieved in MeOH/HBF(4), but, in MeOH alone, acetylide complex 11 is produced from 10. In the absence of MeOH, cyclization of 10, induced by HBF(4), is followed by fluorination to afford complex 13. Crystal structures of 6 and 12 a' were determined by single-crystal diffraction analysis.