Radiosynthesis of the norepinephrine transporter tracer [F-18]NS12137 via copper-mediated F-18-labelling

[F-18]NS12137 (exo-3-[(6-[F-18]fluoro-2-pyridyl)oxy]8-azabicyclo[3.2.1]octane) is a highly selective norepinephrine transporter (NET) tracer. NETs are responsible for the reuptake of norepinephrine and dopamine and are linked to several neurodegenerative and neuropsychiatric disorders. The aim of this study was to develop a copper-mediated F-18-fluorination method for the production of [F-18]NS12137 with straightforward synthesis conditions and high radiochemical yield and molar activity. [F-18]NS12137 was produced in two steps. Radiofluorination of [F-18]NS12137 was performed via a copper-mediated pathway starting with a stannane precursor and using [F-18]F- as the source of the fluorine-18 isotope. Deprotection was performed via acid hydrolysis. The radiofluorination reaction was nearly quantitative as was the deprotection based on HPLC analysis. The radiochemical yield of the synthesis was 15.1 +/- 0.5%. Molar activity of [F-18]NS12137 was up to 300 GBq/mu mol. The synthesis procedure is straightforward and can easily be automated and adapted for clinical production

Fast and efficient copper-mediated 18F-fluorination of arylstannanes, aryl boronic acids, and aryl boronic esters without azeotropic drying

BackgroundCopper-mediated radiofluorination is a straightforward method to produce a variety of [18F]fluoroarenes and [18F]fluoroheteroarenes. To minimize the number of steps in the production of 18F-labelled radiopharmaceuticals, we have developed a short and efficient azeotropic drying-free 18F-labelling method using copper-mediated fluorination. Our goal was to improve the copper-mediated method to achieve wide substrate scope with good radiochemical yields with short synthesis time.ResultsSolid phase extraction with Cu (OTf)2 in dimethylacetamide is a suitable activation method for [18F]fluoride. Elution efficiency with Cu (OTf)2 is up to 79% and radiochemical yield (RCY) of a variety of model molecules in the crude reaction mixture has reached over 90%. Clinically relevant molecules, norepinephrine transporter tracer [18F]NS12137 and monoamine transporter tracer [18F]CFT were produced with 16.5% RCY in 98 min and 5.3% RCY in 64 min, respectively.ConclusionsCu (OTf)2 is a suitable elution agent for releasing [18F]fluoride from an anion exchange cartridge. The method is fast and efficient and the Cu-complex is customizable after the release of [18F]fluoride. Alterations in the [18F]fluoride elution techniques did not have a negative effect on the subsequent labelling reactions. We anticipate this improved [18F]fluoride elution technique to supplant the traditional azeotropic drying of [18F]fluoride in the long run and to concurrently enable the variations of the copper-complex.</div

Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients

Purpose Short-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [F-18]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism.Methods Twenty-five men with newly diagnosed treatment-naive metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [F-18]PSMA-1007 PET/CT immediately before and 3-4 weeks after ADT initiation (degarelix). Before ADT, [F-18]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as Delta SUVmax.Results All the patients reached castration levels of testosterone at the time of the second [F-18]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (>= 20%) in PSMA uptake, with a median Delta SUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [F-18]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA Delta SUVmax and FDG SUVmax (p Conclusions A heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive.</p

Macrophage Hitchhiking Nanoparticles for the Treatment of Myocardial Infarction:An In Vitro and In Vivo Study

Myocardial infarction (MI) is the leading cause of death worldwide. However, current therapies are unable to restore the function of the injured myocardium. Advanced approaches, such as stimulation of cardiomyocyte (CM) proliferation are promising, but suffer from poor pharmacokinetics and possible systemic adverse effects. Nanomedicines can be a solution to the above-mentioned drawbacks. However, targeting the cardiac tissue still represents a challenge. Herein, a MI-selective precision nanosystem is developed, that relies on the heart targeting properties of atrial natriuretic peptide (ANP) and lin-TT1 peptide-mediated hitchhiking on M2-like macrophages. The system based on pH-responsive putrescine-modified acetalated dextran (Putre-AcDEX) nanoparticles, shows biocompatibility with cultured cardiac cells, and ANP receptor-dependent interaction with CMs. Moreover, treatment with nanoparticles (NPs) loaded with two pleiotropic cellular self-renewal promoting compounds, CHIR99021 and SB203580, induces a 4-fold increase in bromodeoxyuridine (BrdU) incorporation in primary cardiomyocytes compared to control. In vivo studies confirm that M2-like macrophages targeting by lin-TT1 peptide enhances the heart targeting of ANP. In addition, NP administration does not alter the immunological profile of blood and spleen, showing the short-term safety of the developed system in vivo. Overall, the study results in the development of a peptide-guided precision nanosystem for delivery of therapeutic compounds to the infarcted heart

Comparative Evaluation of Anti-HER2 Affibody Molecules Labeled with Cu-64 Using NOTA and NODAGA

Imaging using affi body molecules enables discrimination between breast cancer metastases with high and low expression of HER2, making appropriate therapy selection possible. This study aimed to evaluate if the longer half-life of Cu-64 (T-1/2 = 12.7h) would make Cu-64 a superior nuclide compared to Ga-68 for PET imaging of HER2 expression using affibody molecules. The synthetic ZHER2: S1 affibody molecule was conjugated with the chelators NOTA or NODAGA and labeled with Cu-64. The tumor-targeting properties of Cu-64-NOTA-ZHER2: S1 and Cu-64-NODAGA-ZHER2: S1 were evaluated and compared with the targeting properties of Ga-68-NODAGA-ZHER2: S1 in mice. Both 64 Cu-NOTA-ZHER2: S1 and Cu-64-NODAGA-ZHER2: S1 demonstrated specific targeting of HER2-expressing xenografts. At 2 h after injection of Cu-64-NOTA-ZHER2: S1, Cu-64-NODAGA-ZHER2: S1, and Ga-68-NODAGAZHER2: S1, tumor uptakes did not differ significantly. Renal uptake of Cu-64-labeled conjugateswas dramatically reduced at 6 and 24 h after injection. Notably, radioactivity uptake concomitantly increased in blood, lung, liver, spleen, and intestines, which resulted in decreased tumor-to-organ ratios compared to 2 h postinjection. Organ uptake was lower for Cu-64-NODAGA-ZHER2: S1. The most probable explanation for this biodistribution pattern was the release and redistribution of renal radiometabolites. In conclusion, monoamide derivatives of NOTA and NODAGA may be suboptimal chelators for radiocopper labeling of anti-HER2 affibody molecules and, possibly, other scaffold proteins with high renal uptake