Maillard reaction of (18)F-FDG with biological amines results in the formation of (18)F-fluorodeoxyglycosylamines ((18)F-FDGly) as pseudo-Amadori products. To increase in vivo stability, we report the reductive amination of FDGly to provide reduced fluorodeoxyglucamines (FDGlu). (18)F-Fluorodeoxyglucamines ((18)F-FDGlu), resulting from linking (18)F-FDG (hydrophilic) to lipophilic molecules containing amine group may be useful as positron emission tomography (PET) imaging agents. Two amine derivatives, 7-chloro-8-hydroxy-3-methyl-l-(3'-aminophenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine (SCH 38548 for dopamine D1 receptors) and BTA-0 (for Aβ amyloid) were reacted with FDG under reductive amination conditions to yield stable products, FDGluSCH and FDGluBTA. FDGluSCH had high binding affinity to rat brain dopamine D1 receptors with a Ki of 19.5 nM while FDGluBTA had micromolar affinity for human frontal cortex Aβ plaques. (18)F-FDGluSCH was prepared in low to modest radiochemical yields and preliminary results showed binding to the rat striatum in brain slices. In vivo stability of(18)F-FDGluSCH needs to be determined. Our results suggest that (18)F-FDG is a useful 'radioactive synthon' for PET radiotracer development. Its usefulness will have to be determined on the basis of the structure-activity relationship of the target molecule.

The Maillard reaction of sugars and amines resulting in the formation of glycosylamines and Amadori products is of biological significance, for drug delivery, role in central nervous system, and other potential applications. We have examined the interaction of (18) F-fluorodeoxyglucose ((18) F-FDG) with biological amines to study the formation of (18) F-fluorodeoxyglycosylamines ((18) F-FDGly). Respective amines N-allyl-2-aminomethylpyrrolidine (NAP) and 2-(4'-aminophenyl)-6-hydroxybenzothiazole (PIB precursor) were mixed with FDG to provide glycosylamines, FDGNAP and FDGBTA. Radiosynthesis using (18) F-FDG (2-5 mCi) was carried out to provide (18) F-FDGNAP and (18) F-FDGBTA. Binding of FDGBTA and (18) F-FDGBTA was evaluated in human brain sections of Alzheimer's disease (AD) patients and control subjects using autoradiography. Both FDGNAP and FDGBTA were isolated as stable products. Kinetics of (18) F-FDGNAP reaction indicated a significant product at 4 h (63% radiochemical yield). (18) F-FDGBTA was prepared in 57% yield. Preliminary studies of FDGBTA showed displacement of (3) H-PIB (reduced by 80%), and (18) F-FDGBTA indicated selective binding to Aβ-amyloid plaques present in postmortem AD human brain, with a gray matter ratio of 3 between the AD patients and control subjects. We have demonstrated that (18) F-FDG couples with amines under mild conditions to form (18) F-FDGly in a manner similar to click chemistry. Although these amine derivatives are stable in vitro, stability in vivo and selective binding is under investigation.

Objective

Increasing efforts are being made towards pharmacologic activation of brown adipose tissue (BAT) in animals and humans for potential use in the treatment of obesity and diabetes. We and others have reported a number of animal studies using either experimental or therapeutic drugs. There are now efforts to translate these findings to human studies. The goal of this review is to evaluate the various drugs currently being used that have the potential for BAT activation.

Methods

Drugs were classified into 4 classes based on their mechanism of action. Class 1 drugs include the use of β3 adrenoceptor agonists for BAT activation. Class 2 drugs include drugs that affect norepinephrine levels and activate BAT with the potential of reducing obesity. Class 3 includes activators of peroxisome proliferator-activated receptor-γ in pursuit of lowering blood sugar, weight loss and diabetes and finally Class 4 includes natural products and other emerging drugs with limited information on BAT activation and their effects on diabetes and weight loss.

Results

Class 1 drugs are high BAT activators followed by Class 2 and 3. Some of these drugs have now been extended to diabetes and obesity animal models and human BAT studies. Drugs in Class 3 are used clinically for Type 2 diabetes, but the extent of BAT involvement is unclear.

Conclusion

Further studies on the efficacy of these drugs in diabetes and measuring their effects on BAT activation using noninvasive imaging will help in establishing a clinical role of BAT.

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) and Aβ plaque/α4β 2* nicotinic acetylcholine receptors (nAChR). These novel dual agents may be able to efflux Aβ plaques via the paravascular (glymphatic) pathways. 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 nifrolidine (NIF) was used for α4β 2* nAChRs. Aβ plaque/α4β 2* nAChR dual agent, FA-NIF (GKS-007) exhibited IC₅₀ = 3-6 nM for α4β 2* nAChRs in [³H]cytisine-radiolabeled thalamus and frontal cortex in rat brain slices. In postmortem human AD frontal cortex, Aβ plaques labeled with [³H]PIB, FEX-CUR showed a 35% reduction in gray matter (GM)/white matter (WM) [³H]PIB binding, while CUR alone showed a 50% reduction. In vivo biodistribution studies are required of the Aβ-Pgp and Aβ-α4β 2* nAChRs dual targeting agents in order to evaluate their potential as therapeutic approaches for reducing brain Aβ plaques.

Background

We have investigated β3-adrenoceptor agonist mediated brown adipose tissue (BAT) activation using (18)F-FDG PET/CT in Zucker lean (ZL) and obese (ZF) rats.

Methods

(18)F-FDG was injected into ZL and ZF rats pretreated with saline or agonist CL316,243 for scans. (18)F-FDG metabolic activity was computed as standard uptake values.

Results

CL316,243 in ZL activated BAT up to 4-fold compared to saline, while ZF BAT was only up by 2 fold. The decreased activation was consistent with lower β3-adrenoceptor levels in ZF rats.

Conclusions

The genetically modified ZL and ZF rats may provide a useful rat model to evaluate the significance of β3-adrenoceptor agonist-induced BAT activation in obesity.