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Abstract Manganese-52 is gaining interest as an isotope for PET imaging due to its desirable decay and chemical properties for radiopharmaceutical development. Somatostatin receptor 2 (SSTR2) is significantly overexpressed by neuroendocrine tumors (NETs) and is an important target for nuclear imaging and therapy. As an agonist, [68Ga]Ga-DOTATATE has demonstrated significant internalization upon interaction with receptor ligands, whereas [68Ga]Ga-DOTA-JR11(as an antagonist) exhibits limited internalization but better pharmacokinetics and increased tumor uptake. The goal of this study was to label both DOTATATE and DOTA-JR11 peptides with 52Mn in high radiochemical yields (RCY) and sufficient specific activity. A comparison of these two compounds was performed in in vitro and in vivo studies in animals with somatostatin receptor-positive xenografts to characterize differences in cell, tumor, and tissue uptake. Radiolabeling of DOTATATE and DOTA-JR11 was carried out by combining varying concentrations of the peptides with [52Mn]MnCl2. In vitro stability of the radiotracers was determined in mouse serum. In vitro cell uptake and internalization assays were performed in SSTR2 + AR42J cells and negative controls. In vivo biodistribution and longitudinal PET imaging was evaluated in mice bearing AR42J tumors. Both [52Mn]Mn-DOTATATE and [52Mn]Mn-DOTA-JR11 showed affinity for SSTR2 in AR42J cells. However, the uptake of [52Mn]Mn-DOTATATE was higher (11.95 ± 0.71%/ mg) compared to [52Mn]Mn-DOTA-JR11 (7.31 ± 0.38%/ mg) after 2 h incubation. After 4 h incubation, 53.13 ± 1.83% of the total accumulated activity of [52Mn]Mn-DOTATATE was internalized, whereas only 20.85 ± 0.59% of the total accumulated activity of [52Mn]Mn-DOTA-JR11 was internalized. The PET images revealed similar biodistribution results, with [52Mn]Mn-DOTATATE showing a significant tumor uptake of 11.16 ± 2.97% ID/g, while [52Mn]Mn-DOTA-JR11 exhibited a lower tumor uptake of 2.11 ± 0.30% ID/g 4 h post-injection. The synthesis of both radiotracers was accomplished with high RCY and purity. The cell uptake and internalization of [52Mn]Mn-DOTATATE showed higher levels compared to [52Mn]Mn-DOTA-JR11. PET images of the radiotracers in AR42J tumor bearing mice demonstrated similar biodistribution in all organs except the tumor, with [52Mn]Mn-DOTATATE showing higher tumor uptake compared to [52Mn]Mn-DOTA-JR11. The variations in the properties of these tracers could be used to guide further imaging and treatment studies.

Purpose: Due to their long circulation time in the blood, monoclonal antibodies (mAbs) such as trastuzumab, are usually radiolabeled with long-lived positron emitters for the development of agents for Positron Emission Tomography (PET) imaging. Manganese-52 (52Mn, t1/2 = 5.6 d, β+ = 29.6%, E(βave) = 242 keV) is suitable for imaging at longer time points providing a complementary technique to Zirconium-89 (89Zr, t1/2 = 3.3 d, β+ = 22.7%, E(βave) = 396 keV)) because of its long half-life and low positron energy. To exploit these properties, we aimed to investigate suitable bifunctional chelators that could be readily conjugated to antibodies and labeled with 52Mn under mild conditions using trastuzumab as a proof-of-concept. Procedures: Trastuzumab was incubated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 1-Oxa-4,7,10-tetraazacyclododecane-5-S-(4-isothiocyantobenzyl)-4,7,10-triacetic acid (p-SCN-Bn-Oxo-DO3A), and 3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA) at a tenfold molar excess. The immunoconjugates were purified, combined with [52Mn]MnCl2 at different ratios, and the labeling efficiency was assessed by iTLC. The immunoreactive fraction of the radiocomplex was determined through a Lindmo assay. Cell studies were conducted in HER2 + (BT474) and HER2- (MDA-MB-468) cell lines followed by in vivo studies. Results: Trastuzumab-Oxo-DO3A was labeled within 30 min at 37 °C with a radiochemical yield (RCY) of 90 ± 1.5% and with the highest specific activity of the chelators investigated of 16.64 MBq/nmol. The labeled compound was purified with a resulting radiochemical purity of > 98% and retained a 67 ± 1.2% immunoreactivity. DOTA and PCTA immunoconjugates resulted in < 50 ± 2.5% (RCY) with similar specific activity. Mouse serum stability studies of [52Mn]Mn-Oxo-DO3A-trastuzumab showed 95% intact complex for over 5 days. Cell uptake studies showed higher uptake in HER2 + (12.51 ± 0.83% /mg) cells compared to HER2- (0.85 ± 0.10%/mg) cells. PET images of mice bearing BT474 tumors showed high tumor uptake that was consistent with the biodistribution (42.02 ± 2.16%ID/g, 14 d) compared to MDA-MB-468 tumors (2.20 ± 0.80%ID/g, 14 d). Additionally, both models exhibited low bone uptake of < 1% ID/g. Conclusion: The bifunctional chelator p-SCN-Bn-Oxo-DO3A is promising for the development of 52Mn radiopharmaceuticals as it was easily conjugated, radiolabeled at mild conditions, and illustrated stability for a prolonged duration both in vitro and in vivo. High-quality PET/CT images of [52Mn]Mn-Oxo-DO3A-trastuzumab were obtained 14 d post-injection. This study illustrates the potential of [52Mn]Mn-Oxo-DO3A for the evaluation of antibodies using PET imaging. [ABSTRACT FROM AUTHOR]

Abstract Background The integration of positron emission tomography (PET) and magnetic resonance imaging (MRI) holds promise for advancing diagnostic imaging capabilities. The METRICS project aims to develop cyclotron-driven production of 52Mn for PET/MRI imaging. Results Using the 52Cr(p,n)52Mn reaction, we designed chromium metal targets via Spark Plasma Sintering and developed a separation procedure for isolating 52Mn. Labeling tests were conducted with traditional chelators (i.e. S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid) and the 1.4-dioxa-8-azaspiro[4.5]decane-8- carbodithioate ligand to produce radioactive complexes suitable for PET/MRI applications. Our methodology yielded high-quality 52Mn suitable for PET radiopharmaceuticals and PET/MRI imaging. Preliminary studies on phantom imaging using microPET and clinical MRI demonstrated the efficacy of our approach. Conclusions The developed technology offers a promising avenue for producing 52Mn and enhancing PET/MRI imaging capabilities. Further in vivo investigations are warranted to evaluate the potential advantages of this hybrid imaging technique.

Background: The integration of positron emission tomography (PET) and magnetic resonance imaging (MRI) holds promise for advancing diagnostic imaging capabilities. The METRICS project aims to develop cyclotron-driven production of 52Mn for PET/MRI imaging. Results: Using the 52Cr(p,n)52Mn reaction, we designed chromium metal targets via Spark Plasma Sintering and developed a separation procedure for isolating 52Mn. Labeling tests were conducted with traditional chelators (i.e. S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid) and the 1.4-dioxa-8-azaspiro[4.5]decane-8- carbodithioate ligand to produce radioactive complexes suitable for PET/MRI applications. Our methodology yielded high-quality 52Mn suitable for PET radiopharmaceuticals and PET/MRI imaging. Preliminary studies on phantom imaging using microPET and clinical MRI demonstrated the efficacy of our approach. Conclusions: The developed technology offers a promising avenue for producing 52Mn and enhancing PET/MRI imaging capabilities. Further in vivo investigations are warranted to evaluate the potential advantages of this hybrid imaging technique. [ABSTRACT FROM AUTHOR]

Manganese porphyrins have several therapeutic/imaging applications, including their use as radioprotectants (in clinical trials) and as paramagnetic MRI contrast agents. The affinity of porphyrins for lipid bilayers also makes them candidates for cell/liposome labelling. We hypothesised that metalation with the positron emission tomography (PET) radionuclide 52Mn (t 1/2 = 5.6 d) would allow long-term in vivo biodistribution studies of Mn-porphyrins, as well as a method to label and track cells/liposomes, but methods for fast and efficient radiolabelling are lacking. Several porphyrins were produced and radiolabelled by addition to neutralised [52Mn]MnCl 2 and heating using a microwave (MW) synthesiser, and compared with non-MW heating. MW radiosynthesis allowed >95 % radiochemical yields (RCY) in just 1 h. Conversely, non-MW heating at 70 °C for 1 h resulted in low RCY (0–25 % RCY) and most porphyrins did not reach radiolabelling completion after 24 h. Formation of the 52Mn-complexes were confirmed with radio-HPLC by comparison with their non-radioactive 55Mn counterparts. Following this, several [52Mn]Mn-porphyrins were used to radiolabel liposomes resulting in 75–86 % labelling efficiency (LE). Two lead [52Mn]Mn-porphyrins were taken forward to label MDA-MB-231 cancer cells in vitro , achieving ca. 11 % LE. After 24 h, 32–45 % of the [52Mn]Mn-porphyrins was retained in cells. In contrast to standard methods, MW heating allows the fast synthesis of [52Mn]Mn-porphyrins with >95 % radiochemical yields that avoid purification. [52Mn]Mn-porphyrins also show promising cell/liposome labelling properties. Our reported technique can potentially be exploited for the in vivo imaging of Mn-porphyrin therapeutics, as well as for the accurate in vivo quantification of Mn-porphyrin MRI agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Azospirillum brasilense is a prolific grass-root colonizing bacteria well-known for its ability to promote plant growth in several cereal crops. Here we show that one of the mechanisms of action in boosting plant performance is through increased assimilation of the micronutrient manganese by the host. Using radioactive 52Mn2+ (t½ 5.59 d), we examined the uptake kinetics of this micronutrient in young maize plants, comparing the performance of three functional mutants of A. brasilense, including HM053, a high auxin-producing and high N2-fixing strain; ipdC, a strain with a reduced auxin biosynthesis capacity; and FP10, a strain deficient in N2-fixation that still produces auxin. HM053 had the greatest effect on host 52Mn2+ uptake, with a significant increase seen in shoot radioactivity relative to non-inoculated controls. LA-ICP-MS analysis of root sections revealed higher manganese distributions in the endodermis of HM053-inoculated plants and overall higher manganese concentrations in leaves. Finally, increased leaf manganese concentration stimulated photosynthesis as determined by measuring leaf fixation of radioactive 11CO2 with commensurate increases in chlorophyll concentration. [ABSTRACT FROM AUTHOR]

Manganese-52 ground (52gMn) is a positron emitter and its beneficial properties make it a strong candidate for positron emission tomography (PET) imaging. Furthermore, the PET isotope 52gMn has been proposed as a suitable candidate for combination with proteins and antibodies. Moreover, Mn2+ has a paramagnetic property, thus the Mn isotope is ideal for use in bimodal PET/magnetic resonance (MR) images as a traceable nuclide, that can provide anatomical, molecular and physiological information of tissues. In this work, the theoretical calculation of the cross-section to produce 52Mn based on EMPIRE 3.2.2 code was carried out, focusing the attention on the optimization of the code parameters. The calculated cross-sections, obtained considering the effect of different level density models of the code, were compared with the experimental ones, to produce 52Mn isotopes by deuteron beam irradiation in the energy range up to 35 MeV on natCr target. At the same time, the co-produced 54Mn, 51Cr and 48V from natCr(d,X) nuclear reactions have been investigated. The results are also compared with the data taken from the online TENDL library of different versions. [ABSTRACT FROM AUTHOR]

Azospirillum brasilense is a prolific grass-root colonizing bacteria well-known for its ability to promote plant growth in several cereal crops. Here we show that one of the mechanisms of action in boosting plant performance is through increased assimilation of the micronutrient manganese by the host. Using radioactive 52Mn2+ (t½ 5.59 d), we examined the uptake kinetics of this micronutrient in young maize plants, comparing the performance of three functional mutants of A. brasilense, including HM053, a high auxin-producing and high N2-fixing strain; ipdC, a strain with a reduced auxin biosynthesis capacity; and FP10, a strain deficient in N2-fixation that still produces auxin. HM053 had the greatest effect on host 52Mn2+ uptake, with a significant increase seen in shoot radioactivity relative to non-inoculated controls. LA-ICP-MS analysis of root sections revealed higher manganese distributions in the endodermis of HM053-inoculated plants and overall higher manganese concentrations in leaves. Finally, increased leaf manganese concentration stimulated photosynthesis as determined by measuring leaf fixation of radioactive 11CO2 with commensurate increases in chlorophyll concentration.

Manganese-52 is gaining interest as an isotope for PET imaging due to its desirable decay and chemical properties for radiopharmaceutical development. Somatostatin receptor 2 (SSTR2) is significantly overexpressed by neuroendocrine tumors (NETs) and is an important target for nuclear imaging and therapy. As an agonist, [ 68 Ga]Ga-DOTATATE has demonstrated significant internalization upon interaction with receptor ligands, whereas [ 68 Ga]Ga-DOTA-JR11(as an antagonist) exhibits limited internalization but better pharmacokinetics and increased tumor uptake. The goal of this study was to label both DOTATATE and DOTA-JR11 peptides with 52 Mn in high radiochemical yields (RCY) and sufficient specific activity. A comparison of these two compounds was performed in in vitro and in vivo studies in animals with somatostatin receptor-positive xenografts to characterize differences in cell, tumor, and tissue uptake. Radiolabeling of DOTATATE and DOTA-JR11 was carried out by combining varying concentrations of the peptides with [ 52 Mn]MnCl 2 . In vitro stability of the radiotracers was determined in mouse serum. In vitro cell uptake and internalization assays were performed in SSTR2 + AR42J cells and negative controls. In vivo biodistribution and longitudinal PET imaging was evaluated in mice bearing AR42J tumors. Both [ 52 Mn]Mn-DOTATATE and [ 52 Mn]Mn-DOTA-JR11showed affinity for SSTR2 in AR42J cells. However, the uptake of [ 52 Mn]Mn-DOTATATE was higher (11.95 ± 0.71%/ mg) compared to [ 52 Mn]Mn-DOTA-JR11 (7.31 ± 0.38%/ mg) after 2 h incubation. After 4 h incubation, 53.13 ± 1.83% of the total activity of [ 52 Mn]Mn-DOTATATE was internalized, whereas only 20.85 ± 0.59% of the total activity of [ 52 Mn]Mn-DOTA-JR11 was internalized. The PET images revealed similar biodistribution results, with [ 52 Mn]Mn-DOTATATE showing a significant tumor uptake of 11.16 ± 2.97% ID/g, while [ 52 Mn]Mn-DOTA-JR11 exhibited a lower tumor uptake of 2.11 ± 0.30% ID/g 4 h post-injection. The synthesis of both radiotracers was accomplished with high RCY and purity. The cell uptake and internalization of [ 52 Mn]Mn-DOTATATE showed higher levels compared to [ 52 Mn]Mn-DOTA-JR11. PET images of the radiotracers in AR42J tumor bearing mice demonstrated similar biodistribution in all organs except the tumor, with [ 52 Mn]Mn-DOTATATE showing higher tumor uptake compared to [ 52 Mn]Mn-DOTA-JR11. The variations in properties of these tracers could be used to guide further imaging and treatment studies., Competing Interests: Declaration of competing interest The authors declare no known competing interests. Additional Declarations: No competing interests reported.

Due to its decay and chemical properties, interest in manganese-52 has increased for development of long-lived PET radiopharmaceuticals. Its long half-life of 5.6 days, low average positron energy (242 keV), and sufficient positron decay branching ratio make it suitable for radiolabeling macromolecules for investigating slow biological processes. This work aims to establish suitable chelators for manganese-52 that can be radiolabeled at mild conditions through the evaluation of commercially available chelators. Manganese-52 was produced through the nuclear reaction NatCr(p,n)52Mn by irradiation of natural chromium targets on a TR24 cyclotron followed by purification through ion exchange chromatography. The radiolabeling efficiencies of chelators: DOTA, DiAmsar, TETA, DO3A, NOTA, 4′-Formylbenzo-15-crown-5, Oxo-DO3A, and DFO, were assessed by investigating the impact of pH, buffer type, and temperature. In vitro stability of [52Mn]Mn(DO3A)−, [52Mn]Mn(Oxo-DO3A)−, and [52Mn]Mn(DOTA)2− were evaluated in mouse serum. The radiocomplexes were also evaluated in vivo in mice. Crystals of [Mn(Oxo-DO3A)]− were synthesized by reacting Oxo-DO3A with MnCl 2 and characterized by single crystal X-ray diffraction. Yields of 185 ± 19 MBq (5.0 ± 0.5 mCi) (n = 4) of manganese-52 were produced at the end of a 4 h, 15 μA, bombardment with 12.5 MeV protons. NOTA, DO3A, DOTA, and Oxo-DO3A chelators were readily radiolabeled with >96 % radiochemical purity at all conditions. Manganese radiocomplexes of Oxo-DO3A, DOTA, and DO3A remained stable in vitro up to 5 days and exhibited different biodistribution profiles compared to [52Mn]MnCl 2. The solid-state structure of Mn-Oxo-DO3A complex was determined by single-crystal X-ray diffraction. DO3A and Oxo-DO3A are suitable chelators for manganese-52 which are readily radiolabeled at mild conditions with high molar activity, and demonstrate both in vitro and in vivo stability. Radiolabeling and biodistribution of [52Mn]Mn-Chelates in mice. [Display omitted] [ABSTRACT FROM AUTHOR]

MRI has been extensively used in neurodegenerative disorders, such as Alzheimer’s disease (AD), frontal-temporal dementia (FTD), mild cognitive impairment (MCI), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). MRI is important for monitoring the neurodegenerative components in other diseases such as epilepsy, stroke and multiple sclerosis (MS). Manganese enhanced MRI (MEMRI) has been used in many preclinical studies to image anatomy and cytoarchitecture, to obtain functional information in areas of the brain and to study neuronal connections. This is due to Mn2+ ability to enter excitable cells through voltage gated calcium channels and be actively transported in an anterograde manner along axons and across synapses. The broad range of information obtained from MEMRI has led to the use of Mn2+ in many animal models of neurodegeneration which has supplied important insight into brain degeneration in preclinical studies. Here we provide a brief review of MEMRI use in neurodegenerative diseases and in diseases with neurodegenerative components in animal studies and discuss the potential translation of MEMRI to clinical use in the future.

Liposomes are nanoparticles used in drug delivery that distribute over several days in humans and larger animals. Radiolabeling with long-lived positron emission tomography (PET) radionuclides, such as manganese-52 ( 52 Mn, T½ = 5.6 days), allow the imaging of this biodistribution. We report optimized protocols for radiolabeling liposomes with 52 Mn, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 ( 64 Cu, T½ = 12.7 h) through conventional means. The chelator DOTA was used in all cases. The in vivo stability of radiometal chelates is widely debated but studies that mimic a realistic in vivo setting are lacking. Therefore, we employed these four radiolabeled liposome types as platforms to demonstrate a new concept for such in vivo evaluation, here of the chelates 52 Mn-DOTA and 64 Cu-DOTA. This was done by comparing “shielded” remote-loaded with “exposed” surface labeled variants in a CT26 tumor-bearing mouse model. Remote loading (90 min at 55 °C) and surface labeling (55 °C for 2 h) of 52 Mn gave excellent radiolabeling efficiencies of 97–100% and 98–100% respectively, and the liposome biodistribution was imaged by PET for up to 8 days. Liposomes with surface-conjugated 52 Mn-DOTA exhibited a significantly shorter plasma half-life (T ½ = 14.4 h) when compared to the remote-loaded counterpart (T ½ = 21.3 h), whereas surface-conjugated 64 Cu-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2 ± 2.9 h versus 20.3 ± 1.2 h). From our data, we conclude the successful remote-loading of liposomes with 52 Mn, and furthermore that 52 Mn-DOTA may be unstable in vivo whereas 64 Cu-DOTA appears suitable for quantitative imaging. [ABSTRACT FROM AUTHOR]

Cyclotron-based radionuclides production by using solid targets has become important in the last years due to the growing demand of radiometals, e.g., 68Ga, 89Zr, 43/47Sc, and 52/54Mn. This shifted the focus on solid target management, where the first fundamental step of the radiochemical processing is the target dissolution. Currently, this step is generally performed with commercial or home-made modules separated from the following purification/radiolabelling modules. The aim of this work is the realization of a flexible solid target dissolution system to be easily installed on commercial cassette-based synthesis modules. This would offer a complete target processing and radiopharmaceutical synthesis performable in a single module continuously. The presented solid target dissolution system concept relies on an open-bottomed vial positioned upon a target coin. In particular, the idea is to use the movement mechanism of a syringe pump to position the vial up and down on the target, and to exploit the heater/cooler reactor of the module as a target holder. All the steps can be remotely controlled and are incorporated in the cassette manifold together with the purification and radiolabelling steps. The performance of the device was tested by processing three different irradiated targets under different dissolution conditions. [ABSTRACT FROM AUTHOR]

The positron emitter 52gMn is used for the Positron Emission Tomography - PET imaging.In this work we investigate the nuclear reactions for production of 52gMn and 54Mn induced by deuteron beams on natural chromium targets at energies up to E d = 28 MeV using the stacked-foils activation technique. We calculate the thick target yields for 52gMn and for the radionuclidic impurity 54Mn, and we compare the radionuclidic purity of 52gMn with that achievable in proton activation of Cr. The cross-sections of the reactions natCr(d,pxn)51Cr and natCr(d,x)48V are also presented. • Cross-sections of the natCr (d,x)52gMn,54Mn, 51Cr, and 48V were measured up to 28 MeV. • Production yield of 52gMn and 54Mn radionuclides was determined. • Radionuclidic purity of 52gMn was calculated. • 52gMn radionuclidic purity with deuteron beam was compared with the proton one. [ABSTRACT FROM AUTHOR]

Manganese is one of the most important essential micronutrients for the plants. To monitor its uptake and transport by radioactive tracking is a powerful method due to the no carrier added 52Mn in 10−12 moldm−3 concentration range. The generally used method is to measure the radioactivity of cut parts of plants by gamma-spectrometry. Only few studies reported about noninvasive measurement, using pairs of detectors connected in coincidence. We use a full ring MiniPET machine for this purpose to dynamically visualize the uptake and distribution of the radionuclide in 4D. The results are controlled with the conventional gamma spectroscopy after chopping the plants into six parts. The study of stress tolerance initiated by PEG 6000 in different hybrids of maize is also presented as possible application for the phenotyping of plants by PET camera. • Manganese uptake was followed by a full ring miniPET camera. • Two maize hybrids were distinguished by their manganese uptake. • The hybrids were distinguished under drought conditions by their manganese uptake. [ABSTRACT FROM AUTHOR]

With the increasing focus on a more personalized approach to medicine using imaging techniques to select patients for targeted treatment or theranostic strategies, interest in the development of new radionuclides is expanding. Through the development of production and radiochemistry techniques, several new radiometals are being added to the toolbox of the nuclear imaging community. 43,44g,m Sc, 52g Mn, and 45 Ti are all emerging transition metal radionuclides and will be discussed in this short review. Each of these nuclides has unique imaging characteristics and shows promise for the development of new molecular imaging agents., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)