In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.

A mixture of 2-(di-tert-butylphosphino)biphenyl and dicarbonylacetonato rhodium(I) provides an effective catalyst system for the addition of alkynes to aldehydes and activated ketones. In contrast to the more common zinc-catalyzed processes, enolizable 1,2-dicarbonyls are excellent substrates for these rhodium-catalyzed additions. This reaction allows for the formation of propargylic alcohols under mild conditions, tolerating many functional groups (such as carboxylic acids) that are incompatible with other methods. Little selectivity was observed in cases of unsymmetrical 1,2-diketones. Addition of alkynes to aldehydes with an adjacent chirality center usually provides the Felkin addition product with excellent selectivity in some cases. Studies on the catalyst structure show that both the beta-diketonate and a carbon monoxide ligand appear to be bound to the active catalyst. The use of chiral phosphines to induce asymmetry in the propargyl alcohol products provided low enantioselectivity, which may be due to the phosphine having a distal relationship to the reacting centers. Modification of other ligands, such as the beta-diketonate, appears to be a more promising avenue for the development of an enantioselective variant.

A novel fluorine-18 prosthetic ligand, 5-(1,3-dioxolan-2-yl)-2-(2-(2-(2- fluoroethoxy)ethoxy)ethoxy)pyridine [18F]2, has been synthesized. The prosthetic ligand is formed in high radiochemical yield (rcy = 71 ± 2 %, n = 3) with excellent radiochemical purity (rcp = 99 ± 1 %, n = 3) in a short reaction time (10 min). [18F]2 is a small, neutral, organic complex, easily synthesized in four steps from a readily available starting material. It can be anchored onto a target molecule containing an aminooxy functional group under acidic conditions by way of an oxime bond. We report herein two examples [18F]23 and [18F]24, potential imaging agents for β-amyloid plaques, which were labeled with this prosthetic group. This approach could be used for labeling proteins and peptides containing an aminooxy group. Biodistribution in male ICR mice for both oxime labeled complexes [18F]23 and [18F]24 were compared to that of the known β-amyloid plaque indicator, [18F]-AV-45, florbetapir 1. Oximes [18F]23 and [18F]24 are larger in size and therefore should reduce the blood-brain barrier (BBB) penetration. The brain uptake for oxime [18F]23 appeared to be reduced, but still retained some capability to cross the BBB. Oxime [18F]24 showed promising results after 2 min post injection (0.48 % dose/gram), however the uptake increased after 30 min post injection (0.92 % dose/gram) suggesting an in-vivo decomposition/metabolism of compound [18F]24. We have demonstrated a general protocol for the fluoride-18 labeling with a new prosthetic ligand [18F]2 that is tolerant towards several functional groups and is formed via chemoselective oxime coupling.

Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than two years. A key reason for this high mortality is that the blood–brain barrier (BBB) significantly restricts systemically delivered therapeutics to brain tumors. High-intensity focused ultrasound (HIFU) with microbubbles is a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. Topotecan is a topoisomerase inhibitor used as a chemotherapeutic agent to treat ovarian and small cell lung cancer. Studies have suggested that topotecan can cross the BBB and can be used to treat brain metastases. However, pharmacokinetic data demonstrated that topotecan peak concentration in the brain extracellular fluid after systemic injection was ten times lower than in the blood, suggesting less than optimal BBB penetration by topotecan. We hypothesize that HIFU with microbubbles treatment can open the BBB and significantly increase topotecan concentration in the brain. We radiolabeled topotecan with 11C and acquired static and dynamic positron emission tomography (PET) scans to quantify [11C] topotecan uptake in the brains of normal mice and mice after HIFU treatment. We found that HIFU treatments significantly increased [11C] topotecan brain uptake. Moreover, kinetic analysis of the [11C] topotecan dynamic PET data demonstrated a substantial increase in [11C] topotecan volume of distribution in the brain. Furthermore, we found a decrease in [11C] topotecan brain clearance, confirming the potential of HIFU to aid in the delivery of topotecan through the BBB. This opens the potential clinical application of [11C] topotecan as a tool to predict topotecan loco-regional brain concentration in patients with GBMs undergoing experimental HIFU treatments.

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We have developed a novel F-18 prosthetic ligand named fluoro-PEG-benzaldehyde (FPBA) 1. [18F]-FPBA 1 is formed in situ from its radiolabeled precursor [18F]6. Compound 6 is efficiently synthesized in four steps starting from commercially available 6-bromo-3-pyridine carbaldehyde 2. [18F]-FPBA was evaluated as a prosthetic ligand to radiolabel three cyclic peptides bearing an aminooxy functional group at the N-terminus position. Acetal [18F]6 is purified by either solid-phase extraction (SPE) or reverse-phase HPLC with the overall radiochemical yields (RCY) and radiochemical purity (RCP) in very close agreement. The SPE purification process has the advantage of shorter reaction times (71–87 min for entire reaction sequence), while the use of the reverse-phase HPLC purification process allows the use of up to fifty times less of the expensive synthetic peptides (~ 50 nmol) in the oxime coupling reaction. We have demonstrated an efficient methodology in the production of [18F]-FPBA 1 and demonstrated its use as a prosthetic ligand for the labeling of peptides possessing an aminooxy functional group.

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