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New positron emission tomography (PET) radioligand for imaging ?-1 receptors in living subjects.

ABSTRACT: ?-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([(18)F]FTC-146, [(18)F]13). [(18)F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/?mol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [(18)F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [(18)F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [(18)F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [(18)F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.

SUBMITTER: James ML

PROVIDER: S-EPMC4106900 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects.

James Michelle L ML Shen Bin B Zavaleta Cristina L CL Nielsen Carsten H CH Mesangeau Christophe C Vuppala Pradeep K PK Chan Carmel C Avery Bonnie A BA Fishback James A JA Matsumoto Rae R RR Gambhir Sanjiv S SS McCurdy Christopher R CR Chin Frederick T FT

Journal of medicinal chemistry 20120920 19

σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([(18)F]FTC-146, [(18)F]13). [(18)F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (n = 13) at end of synthesis (EOS). Positron emissi ...[more]

PMID: 22853801

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Project description:UnlabelledThe recent advancement of nanotechnology has provided unprecedented opportunities for the development of nanoparticle enabled technologies for detecting and treating cancer. Here, we reported the construction of a PET trackable organic nanoplatform based on phage particle for targeted tumor imaging.MethodThe integrin ?(v)?(3) targeted phage nanoparticle was constructed by expressing RGD peptides on its surface. The target binding affinity of this engineered phage particle was evaluated in vitro. A bifunctional chelator (BFC) 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) or 4-((8-amino-3,6,10,13,16,19-hexaazabicyclo [6.6.6] icosane-1-ylamino) methyl) benzoic acid (AmBaSar) was then conjugated to the phage surface for (64)Cu(2+) chelation. After (64)Cu radiolabeling, microPET imaging was performed in U87MG tumor model and the receptor specificity was confirmed by blocking experiments.ResultsThe phage-RGD demonstrated target specificity based on ELISA experiment. According to the TEM images, the morphology of the phage was unchanged after the modification with BFCs. The labeling yield was 25 ± 4% for (64)Cu-DOTA-phage-RGD and 46 ± 5% for (64)Cu-AmBaSar-phage-RGD, respectively. At 1 h time point, (64)Cu-DOTA-phage-RGD and (64)Cu-AmBaSar-phage-RGD have comparable tumor uptake (~ 8%ID/g). However, (64)Cu-AmBaSar-phage-RGD showed significantly higher tumor uptake (13.2 ± 1.5 %ID/g, P<0.05) at late time points compared with (64)Cu-DOTA-phage-RGD (10 ± 1.2 %ID/g). (64)Cu-AmBaSar-phage-RGD also demonstrated significantly lower liver uptake, which could be attributed to the stability difference between these chelators. There is no significant difference between two tracers regarding the uptake in kidney and muscle at all time points tested. In order to confirm the receptor specificity, blocking experiment was performed. In the RGD blocking experiment, the cold RGD peptide was injected 2 min before the administration of (64)Cu-AmBaSar-phage-RGD. Tumor uptake was partially blocked at 1 h time point. Phage-RGD particle was also used as the competitive ligand. In this case, the tumor uptake was significantly reduced and the value was kept at low level consistently.ConclusionIn this report, we constructed a PET trackable nanoplatform based on phage particle and demonstrated the imaging capability of these targeted agents. We also demonstrated that the choice of chelator could have significant impact on imaging results of nano-agents. The method established in this research may be applicable to other receptor/ligand systems for theranostic agent construction, which could have an immediate and profound impact on the field of imaging/therapy and lay the foundation for the construction of next generation cancer specific theranostic agents.

Project description:BackgroundSchistosomes are chronic intravascular helminth parasites of humans causing a heavy burden of disease worldwide. Diagnosis of schistosomiasis currently requires the detection of schistosome eggs in the feces and urine of infected individuals. This method unreliably measures disease burden due to poor sensitivity and wide variances in egg shedding. In vivo imaging of schistosome parasites could potentially better assess disease burden, improve management of schistosomiasis, facilitate vaccine development, and enhance study of the parasite's biology. Schistosoma mansoni (S. mansoni) have a high metabolic demand for glucose. In this work we investigated whether the parasite burden in mice could be assessed by positron emission tomography (PET) imaging with 2-deoxy-2[(18)F]fluoro-D-glucose (FDG).Methodology/principal findingsLive adult S. mansoni worms FDG uptake in vitro increased with the number of worms. Athymic nude mice infected with S. mansoni 5-6 weeks earlier were used in the imaging studies. Fluorescence molecular tomography (FMT) imaging with Prosense 680 was first performed. Accumulation of the imaging probe in the lower abdomen correlated with the number of worms in mice with low infection burden. The total FDG uptake in the common portal vein and/or regions of elevated FDG uptake in the liver linearly correlated to the number of worms recovered from infected animals (R(2)?=0.58, P<0.001, n = 40). FDG uptake showed a stronger correlation with the worm burden in mice with more than 50 worms (R(2)?= 0.85, P<0.001, n = 17). Cryomicrotome imaging confirmed that most of the worms in a mouse with a high infection burden were in the portal vein, but not in a mouse with a low infection burden. FDG uptake in recovered worms measured by well counting closely correlated with worm number (R(2)?= 0.85, P<0.001, n = 21). Infected mice showed a 32% average decrease in total FDG uptake after three days of praziquantel treatment (P = 0.12). The total FDG uptake in untreated mice increased on average by 36% over the same period (P = 0.052).ConclusionFDG PET may be useful to non-invasively quantify the worm burden in schistosomiasis-infected animals. Future investigations aiming at minimizing non-specific FDG uptake and to improve the recovery of signal from worms located in the lower abdomen will include the development of more specific radiotracers.

Dataset Information

New positron emission tomography (PET) radioligand for imaging ?-1 receptors in living subjects.

Publications

New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects.

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