Innovation Delivered

Cerebrovascular disease encompasses a range of pathologies that affect different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate altered metabolic processes that are key to their pathogenesis. Positron Emission Tomography (PET) can detect and quantify metabolic processes that are relevant to each facet of cerebrovascular disease. The review article published in the November 2017 issue of Nature Reviews Neurology describes how PET-based imaging of metabolic processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease.

Evans, N. R. et al. PET imaging of the neurovascular interface in cerebrovascular disease. Nat Rev Neurol 13, 676–688 (2017). doi:10.1038/nrneurol.2017.129

PET imaging employs various radioligands to detect physiological processes in vivo. The article written by Nicholas R. Evans, University of Cambridge, Cambridge, UK and his colleagues summaries the radioisotopes of PET ligands used for the following list of cellular or physiological targets of vascular biology, actute ischaemic stroke and small vessel disease:

1. Increased metabolic rate (inflammation): ¹⁸F-FDG
   2. Macrophages: ⁶⁸Ga-DOTATATE (targeting somatostatin receptor type 2)
   3. Microcalcification: ¹⁸F-NaF (hydroapatite)
   4. Hypoxia: ¹⁸F-FMISO (targeting selective reduction in hypoxia)
   5. Macrophages and microglia: ¹¹C-PK11195, ¹¹C-PBR28, ¹⁸F-DPA-714, ¹¹C-vinpocetine, ¹⁸F-GE-180 (all targeting TSPO)
   6. Neurons: ¹¹C-FMZ (GABA-A receptor)
   7. Amyloid: ¹¹C-PiB (analogue of thioflavin T)
   8. Neurons: ¹⁸F-FNDP (epoxide hydrolase enzyme)
   9. Expressed on neurons, astrocytes, microglia and endothelial cells: ¹⁸F-NS14490 (α7 nicotonic acetylcholine receptor)
   10. Apoptosis: ¹⁸F-labeled isatins (caspase 3, caspase 7)

The review article considers sensitivity, specificity, technical considerations and also clinical implications for each radiotracersThe nanoScan PET/MRI3T is an ideal combination of modalities for research of cerebrovascular diseases: structural imaging provided by MRI is co-registered and combined with the PET ability to detect and quantify these pathophysiological processes in vivo. Information obtained from PET studies has helped to shape the understanding of key concepts in cerebrovascular medicine, including vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult. New PET ligands continue to be developed that have superior specificity or that target new processes of interest.

Nanomedicine and Personalized Treatments

Nanomedicine is simply the medical application of nanotechnologies. The idea is the involvement the use of nanoparticles to improve the behaviour of drug substances. The goal is to achieve improvement over conventional chemotherapies. Customized treatments will be required to overcome the issues raised by clinical patient and disease heterogeneity. As one might expect, the same drug will accumulate in tumors at varying concentrations in patients with different cancers. But this also happens in patients with the same kind of cancer. It has to be ensured that drug nanocarriers are really accumulating in the specific tissues to better treat patients. This brings in the necessity of a treatment prediction tool to select the patients most likely to accumulate high amounts of the nanomedicine of interest and hence benefit from nanomedicinal treatment.

Positron Emission Tomography (PET) is such a noninvasive quantitative imaging tool with excellent sensitivity and spatial/temporal resolution required at the whole-body level. Radiolabeling of liposomal nanomedicines with single-photon emission computed tomography (SPECT) radionuclides has been successfully used to study their biodistribution in preclinical and clinical studies, but SPECT imaging suffers from lower sensitivity and temporal/spatial resolution than PET. However, an ideal PET radiolabeling method viable for both preclinical and clinical imaging wasn’t explored before. Rafael T. M. de Rosales, Alberto Gabizon and colleagues at King’s College London and the Shaare Zedek Medical Center sought to address this challenge.

Edmonds, S. et al. Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines. ACS Nano (2016). doi:10.1021/acsnano.6b05935

The following Mediso systems were used to conduct the animal imaging studies: nanoScan PET/CT and NanoSPECT/CT Silver upgrade. Both systems are equipped with the MultiCell animal handling and monitoring system , thus enabling a combined PET-CT/SPECT-CT imaging strategy. Interestingly both PET and SPECT were performed in the same animals (by moving the same bed from scanner from scanner, while the animals were anesthetized in fixed position) that allowed to image the tumour cells with SPECT and the nanomedicine with PET.

Liposomal Drug PET Radiolabeling Method Development

The researchers introduced a simple and efficient PET radiolabeling method exploiting the metal-chelating properties of certain drugs (e.g., bisphosphonates such as alendronate and anthracyclines such as doxorubicin) and widely used ionophores radiolabeled with long half-life metallic PET isotopes, such as ⁸⁹Zr, ⁵²Mn and ⁶⁴Cu. The labels — and thus the liposomal drugs — could then be tracked using positron emission tomography (PET) to see where they go within the body. The article discusses in details the feasibility and effectiveness of their method, as well as its advantages and limitations, and show its utility for detecting and quantifying the biodistribution of a liposomal nanomedicine containing an aminobisphosphonate in vivo.

In a model of metastatic breast cancer, the researchers demonstrated that their technique allows quantification of the biodistribution of a radiolabeled stealth liposomal nanomedicine. Alendronate (ALD), an aminobisphosphonate, was selected as the radionuclide-binding drug of choice to develop this method for two reasons: (i) known ability to act as metal chelator to form inert coordination complexes with zirconium, copper, and manganese; and (ii) demonstrated anticancer activity and γ−δ T-cell immunotherapy sensitizing properties. The used liposomal formulation is referred to as PLA in the article.

Monitoring Liposomal Nanomedicine Distribution

The biodistribution of the radiolabeled liposomes was monitored using PET imaging with ⁸⁹Zr-PLA in a metastatic mammary carcinoma mouse model established in immunocompromised NSG mice. This cancer model is also traceable by SPECT imaging/fluorescence due to a dual-modality reporter gene, the human sodium iodide symporter (hNIS-tagRFP), that allows sensitive detection of viable cancer tissues (primary tumor and metastases) using SPECT imaging with ^99mTc-pertechnetate and fluorescence during dissection and histological studies. The imaging protocol was as follows: first, mice were injected with 89Zr-PLA (4.6 ± 0.4 MBq) at t = 0 followed by nanoScan PET-CT imaging (liposome biodistribution). The same mice were then injected with ^99mTc-pertechnetate (30 MBq) and imaged by SPECT-CT. The SPECT injection was repeated at t = 24 h, 72 h, and 168 h. It was confirmed by separate phantom studies that the presence of ^99mTc was not affecting the quality/quantification of the PET study. CT images revealed a significant increase in tumor volume during the imaging study. Using the tumor volumes from SPECT and CT, the researchers calculated the percentage of necrotic tumor tissue over time, by subtracting the hNIS-positive volume (SPECT) to the total tumor volume (CT). A PET-CT study was also performed using ⁶⁴Cu-PLA in an ovarian cancer model (SKOV-3/SCID-Beige) over 48 h to test the versatility and capability of the radiolabeling method.

The common MultiCell animal handling and monitoring system (developed by Mediso) on both imaging systems gave the possibility to easily co-register the PET-CT/SPECT-CT and PET/SPECT studies as the animals were moved in co-registered position between the systems.

MIP video (3D, rotating along z-axis) showing co-registration of PET (red signal, 89Zr-PLA) and SPECT (green signal, 99mTcO4-, hNIS positive viable tumour tissue) of representative tumor from the mutimodal PET/SPECT study in the 3E.Δ.NT/NSG model. Both signals/radiotracers accumulate predominantly at the rim of the tumour and areas of low colocalization as well as high co-localization (yellow) are evident.

Imaging with PET in mouse models of breast and ovarian cancer showed the drugs accumulated in tumors and metastatic tissues in varying concentrations and at levels well above those in normal tissues, the researchers report. In one mouse strain, the nanomedicines unexpectedly showed up in uteruses, a result that wouldn’t have been detected without conducting the imaging study, according to the researchers.

Discussion

The results establish that preformed liposomal nanomedicines, including some currently in clinical use, can be efficiently labeled with PET radiometals and tracked in vivo by exploiting the metal affinity and high concentration of the encapsulated drugs. Importantly, the technique allows radiolabeling of preformed liposomal nanomedicines, without modification of their components and without affecting their physicochemical properties.

The versatility, efficiency, simplicity, and GMP compatibility of this method may enable submicrodosing imaging studies of liposomal nanomedicines containing chelating drugs in humans and may have clinical impact by facilitating the introduction of image-guided therapeutic strategies in current and future nanomedicine clinical studies. The ultimate goal is to use non-invasive imaging data to predict how much drug will be delivered to cancer tissues in specific patients, and whether the nanomedicine is reaching all the patient’s tumors in therapeutic concentrations.

Many thanks for Rafael T. M. de Rosales, the last author of the original article.

In the first published article from MSKCC (Carney, B. et al. Non-invasive PET Imaging of PARP1 Expression in Glioblastoma Models. Mol Imaging Biol 1–7 (2015)), using the nanoScan PET/MRI (1T) small animal imaging system, in vivo whole body PET/MRI imaging of [¹⁸F]PARPi in orthotopic brain tumor-bearing mice is referenced.

[¹⁸F]PARPi is a selective PARP1 imaging agent that can be used to visualize glioblastoma in xenograft and orthotopic mouse models with high precision and good signal/noise ratios offering new opportunities to non-invasively image tumor growth and monitor interventions.

Figure 6 in the article shows coronal views of contrast-enhanced MRI, [¹⁸F]PARPi PET images, and fused PET/MRI of orthotopic U251 MG tumor-bearing mice. In the top row the mouse receivied only [¹⁸F]PARPi, in the bottom row the mouse receivied [¹⁸F]PARPi after a 500-fold excess of olaparib.

The animals were injected with 200 µCi of [18F]-PARPi and a 20 minutes static PET scan was acquired 2 hours post injection. 200 µL of diluted gadopentate dimegumine in saline solution  was administered intravenously one minute prior to MRI acquisition. Tumor regions were identified on anatomic images acquired using a post-contrast T-weighted spin-echo (SE) acquisition. The co-localization of [¹⁸F]PARPi and tumor in PET/MRI studies was confirmed by ex vivo autoradiography. In PET/MRI fusion images, accumulation in the tumor was co-aligned with the orthotopic tumor on MRI. In mice receiving an injection of olaparib ahead of the radiotracer, the [¹⁸F]PARPi tumor uptake was negligible.

It's important to note that no further or manual co-registration was required at all as the PET/MRI studies performed on the nanoSCan PET/MRI are co-registered by nature due to the common gantry and automated acquisition system. The very same images are displayed in the viewer when the dual-modality study is loaded from the DICOM server after reconstruction. This gives scientists confidence when evaluating multi-modal data; changing animal physiology and data obtained at different times won't distort the findings.

Introduction

This post summarizes the results on a research of a new Zr89 PET tracer for cell labeling. The open access article was published last month in the European Journal of Nuclear Medicine and Molecular Imaging journal:

Charoenphun, P. et al. [89Zr]Oxinate4 for long-term in vivo cell tracking by positron emission tomography. EJNMMI (2014)

The preclinical PET/CT images were acquired on a nanoScan PET/CT in vivo small animal imaging system at King’s College London.

Increasing sensitivity of cell tracking by changing labeling and detection from SPECT to PET

Cell tracking by gamma imaging with radionuclides has been performed clinically for over 30 years and is used for tracking autologous leukocytes to detect sites of infection/inflammation. The standard radiolabelling methodology has been non-specific assimilation of lipophilic, metastable complexes of indium-111 (with oxine) or technetium-99m (with HMPAO). Regenerative medicine and immune cell-based therapies are creating new roles for clinical tracking of these cells. Conventional cell radiolabelling methods have been applied for some of these cell types, but for clinical use new applications will require detection of small lesions and small numbers of cells beyond the sensitivity of traditional gamma camera imaging with In-111 or Tc-99m (e.g. coronary artery disease, diabetes, neurovascular inflammation and thrombus), creating a need for positron-emitting radiolabels to exploit the better sensitivity, quantification and resolution of clinical PET.

So far the search for positron emitting (PET) radiolabels for cells has met with limited success. The near-ubiquitous presence of glucose transporters allows labelling with [18F]-FDG but labelling efficiencies are highly variable, the radiolabel is prone to rapid efflux, and the short half-life (110 min) of F-18 allows only brief tracking. Copper-64 offers a longer (12 h) half-life and efficient cell labelling using lipophilic tracers but rapid efflux of label from cells is a persistent problem and a still longer half-life would be preferred. A “PET analogue” of In-111 oxine, capable of cell tracking over 7 days or more, would be highly desirable but is not yet available.

Zr-89 Oxine: a PET cell radiolabelling agent for long term in vivo cell tracking

This paper describes the first synthesis of Zr-89 oxine, and comparison with In-111 oxine for labelling several cell lines, human leukocytes and tracking of the cancer cell line GFP-5T33 cells in mice. The new lipophilic, metastable complex of Zr-89 can radiolabel a range of cells, independently of specific phenotypes, providing a long-sought solution to the unmet need for a long half-life positron-emitting radiolabel to replace In-111 for cell migration imaging. In addition to the expected advantages (enhanced sensitivity, resolution and quantification) of cell tracking with PET rather than scintigraphy or SPECT, Zr-89 shows less efflux from cells in vitro and in vivo than In-111. GFP-5T33 is a syngeneic murine multiple myeloma model originating from the C57Bl/KaLwRij strain, engineered to express green fluorescent protein (GFP). It was chosen for this work because the fate of the cells after i.v. inoculation is known from the literature. Intravenously injected cells migrate exclusively to the liver, spleen and bone marrow. Furthermore as the radiolabelled cells were GFP positive it was possible to validate the non-invasive images by using flow sorting of the GFP positive cells and negative cells. After flow sorting the authors were able to show that after 7 days in vivo the Zr-89 Oxine cells remained viable for the duration of the study, and that ~95% of radioactivity was present in viable GFP+ cells. The excellent in vivo survival and retention of radioactivity by the cells at 7 days, coupled with the demonstrated ability to acquire useful PET images up to 14 days, significantly extend the typical period over which cells can be tracked by radionuclide imaging with directly labelled cells.

The use of PET Zr-89 oxine for cell tracking could have a dramatic impact in the investigation of infection, inflammation and cell-based therapies in humans.

In the field of highly sophisticated pre-clinical imaging systems we all know that it’s important to publish articles, technical validations and independent peer reviewed performance evaluation papers on instrumentation. Eventually these performance evaluation, characterization or comparison articles make their way into review articles.

The "review article" is one of the most useful tools available for individuals who need to research a certain topic in the rapidly expanding body of scientific literature. According to Huth [1] a "well-conceived review written after careful and critical assessment of the literature is a valuable document” and it spares time for researchers to keep abreast of all published information. A review article should provide a critical appraisal of the subject.

It is extremely difficult to compare the performance of two imaging systems from different vendors if there is no standardized methodology that is independent of the camera design. Such a methodology should be applicable to a wide range of camera models and geometries. Fortunately for the Primary Investigators there is a NEMA standard publication for performance measurements of small animal positron emission tomographs (NEMA Standards Publication NU 4-2008 [2]) since 2008.

I myself have an engineering background and I’m always astonished how creatively sales people can distort the reality (i.e. numbers) in their marketing materials. I started an excel sheet back in 2007 by filling out numerous specifications for every small animal PET systems, either commercial or academic, when we started the design of our nanoScan small animal PET system at Mediso. Currently it lists about 40 pre-clinical systems including variants (while most of them are now obsolete or discontinued, such as the the Siemens Inveon). As part of my position I closely follow the published performance evaluation and review articles.

Balancing a system design is very delicate question – sensitivity and resolution do not walk hand in hand and it’s easy to get lost in the quagmire of different parameters: ultimately the detector design, the basic parameters and image characteristics together define the image quality. Also the image quality of a certain measurement series does not say anything about reproducibility, long term imaging performance, usability and feature sets.

Review of Review Article

My particular problem with instrumentation review articles is that they usually have a limited/selected subset of parameters which subconsciously (or consciously as I will give the benefit of doubt here) can lead to distortion of the reality. My apologies to the authors of the article by Kuntner & Stout, but this latest review article for preclinical PET imaging and may serve as example [3]. It is a really good article and lists various factors affecting the quantification accuracy of small PET systems. It’s a recommended article to read!

In the first table it shows the characteristics of preclinical PET scanners (visit to the link to view the original table)

The article was published on 28 February 2014, and was originally received on 27 November 2013. It references the Mediso’s microPET system based on an article from JNM 2011 [4]. However the performance evaluation of our next generation nanoScan PET was published online on August 29, 2013 in JNM [5]. Fortunately Spinks and his colleagues published a new paper on the quantitative performance of Albira PET with its largest axial FOV variant in February 2014 [6], so the Albira’s characteristics won’t be distorted – their ‘flagship’ variant is also listed. Lack of access to projection data by the researchers, the standard NEMA procedure could not be used for some of their measurements (e.g. sensitivity, scatter fraction, noise-equivalent counts).

Updated comparison table

So let’s include the updated characteristics in our new table and have a closer look on the parameters.

My problems with the original Table 1 in [3]:

1. The ‘ring diameter’ was listed in the comparison table, which is quite non-relevant unless you want disassemble the system. It’s much more useful to list the bore diameter and the transaxial FOV. The bore diameter shows how wide object you can stick into the system, while the transaxial FOV shows that actually where you will collect data from!
2. The resolution values listed are not comparable– some of them were listed according to the NEMA NU-4 2008 standard performed with SSRB+FBP (e.g. Inveon), and some of them with iterative reconstruction methods like OSEM (e.g. Genisys4). The pre-clinical PET NEMA standard allows only the usage of the filtered back projection reconstruction method to measure the resolution. More importantly the results have to show the values in all directions: in the transverse slice in radial and tangential directions and additionally the axial resolution shall be measured across transverse slices at 5, 10, 15 and 25 mm radial distances from the center. Example from [5]:
   
   Currently based on the published literature the nanoScan PET subsystem from Mediso delivers the best resolution values for the NEMA NU-4 2008 measurements – even without using the sophisticated 3D Tera-Tomo Reconstruction engine. Based on the original article the reader may derive the false conclusion that the Genisys4 PET delivers the best resolution – while it’s hardly the situation. The FBP recon values had not been published for Genisys4 so far.
3. The 2D FBP recon provides comparable information on the detector design, but not the system performance! The advanced 3D iterative reconstruction methods allow to incorporate lot of corrections and they provide better spatial resolution, image characteristics – if used properly. Let’s call these resolution values performed by ‘advanced’ reconstruction methods ‘claimed by manufacturer’ values.
4. Please always pay attention to the energy window setting when comparing sensitivity values!

Sensitivity

In the literature sensitivity values for mouse-sized region are listed only for 3 small animal PET systems: Albira, Inveon and nanoScan. For rat-sized object you can find value only for the Mediso’s system.

The Truth Lies in the Details.

References:

1. Edward J. Huth, How to Write and Publish Papers in the Medical Sciences (Williams & Wilkins, 1990).
2. National Electrical Manufacturers Association. NEMA Standard Publication NU 4-2008: Performance Measurements of Small Animal Positron Emission Tomographs. Rosslyn, VA: National Electrical Manufacturers Association; 2008
3. Claudia Kuntner and David B. Stout, “Quantitative Preclinical PET Imaging: Opportunities and Challenges,” Biomedical Physics 2 (2014): 12, doi:10.3389/fphy.2014.00012. http://journal.frontiersin.org/Journal/10.3389/fphy.2014.00012/full
4. Istvan Szanda et al., “National Electrical Manufacturers Association NU-4 Performance Evaluation of the PET Component of the NanoPET/CT Preclinical PET/CT Scanner,” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 52, no. 11 (November 2011): 1741–47, doi:10.2967/jnumed.111.088260. http://jnm.snmjournals.org/content/52/11/1741.long
5. Kálmán Nagy et al., “Performance Evaluation of the Small-Animal nanoScan PET/MRI System,” Journal of Nuclear Medicine, October 1, 2013, jnumed.112.119065, doi:10.2967/jnumed.112.119065. http://jnm.snmjournals.org/content/early/2013/08/26/jnumed.112.119065
6. T. J. Spinks et al., “Quantitative PET and SPECT Performance Characteristics of the Albira Trimodal Pre-Clinical Tomograph,” Physics in Medicine and Biology 59, no. 3 (February 7, 2014): 715, doi:10.1088/0031-9155/59/3/715. http://iopscience.iop.org/0031-9155/59/3/715
7. Qinan Bao et al., “Performance Evaluation of the Inveon Dedicated PET Preclinical Tomograph Based on the NEMA NU-4 Standards,” Journal of Nuclear Medicine 50, no. 3 (2009): 401–8. http://jnm.snmjournals.org/content/50/3/401.short
8. Andrew L. Goertzen et al., “NEMA NU 4-2008 Comparison of Preclinical PET Imaging Systems,” Journal of Nuclear Medicine 53, no. 8 (2012): 1300–1309. http://jnm.snmjournals.org/content/53/8/1300.short
9. Stephen Adler, Jurgen Seidel, and Peter Choyke, “NEMA and Non-NEMA Performance Evaluation of the Bioscan BioPET/CT Pre-Clinical Small Animal Scanner,” Society of Nuclear Medicine Annual Meeting Abstracts 53, no. Supplement 1 (May 1, 2012): 2402. http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/53/1_MeetingAbstracts/2402
10. Ken Herrmann et al., “Evaluation of the Genisys4, a Bench-Top Preclinical PET Scanner,” Journal of Nuclear Medicine, July 1, 2013, doi:10.2967/jnumed.112.114926. http://jnm.snmjournals.org/content/early/2013/04/29/jnumed.112.114926
11. F. Sánchez et al., “Small Animal PET Scanner Based on Monolithic LYSO Crystals: Performance Evaluation,” Medical Physics 39, no. 2 (2012): 643, doi:10.1118/1.3673771. http://link.aip.org/link/MPHYA6/v39/i2/p643/s1&Agg=doi

Development of dual-modality, aluminium hydroxide stabilised magnetic nanoparticles probes is published in the Biomaterials 2014 July issue. The main author of the article titled ‘Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging’ [1] is Dr. Xianjin Cui, member of Philip Blower’s group at King's College London, Division of Imaging Sciences and Biomedical Engineering. The article is a collaboration between researchers from King’s College London (UK), Nottingham University (UK), Aston University (UK), CROmed Ltd. (Hungary). This is an open access article. Download the Article in PDF, Appendix A in Word.

Superparamagnetic nanoparticles

Superparamagnetic nanoparticles (NPs) have been intensively investigated due to their potential applications in biosensors, targeted drug develivery, MRI and localised hyperthermia induction. The problem with these nanoparticles is that they tend to aggregate to minimize the surface energy. Bio-applications require colloidal stability and dispersibility in water and biological environments. There are several methods described in the literature to obtain stable colloids of magnetic nanoparticles. A simple approach is presented in the article to stabilise magnetic nanoparticles by coating them with an Al(OH)3 layer via a hydrolysis process for conjugation. The use of an inorganic shell material introduces stability, functionality (nanoparticle recognised by the macrophage-monocytic system) and water-solubility. The materials, general characterisation, synthesis and radiolabelling are described in the article.

in vivo PET/MR imaging

What is interesting for our blog is that for in vivo PET/MR imaging of the agents on mice were performed on the integrated nanoScan preclinical PET/MRI imaging system installed at the Nanobiotechnology & In Vivo Imaging Center, Semmelweis University in Budapest, Hungary.

The total injected F-18 activity was 0.95 MBq (25.7 microCi). PET scanning was started immediately after injection and continued for 120 min. Acquisition took place in 1–5 coincidence mode with 5 ns coincidence window, 400–600 keV energy window. MR scanning was performed immediately after PET. A 3D expectation maximisation (3D EM) PET reconstruction algorithm (Mediso Tera-Tomo™) was applied to produce PET images including corrections for attenuation and scatter, dead time, decay and randoms. After 8 iterations the reconstruction stopped resulting in images with 0.1 mm voxel size and time frames of 8 × 15 min. The images of the two modalities were fused automatically.

The PET/MRI fused image is presented in the Appendix A. of the article. The injected activity was only 0.95 MBq (25.7 microCi) and the PET images show only 15 minutes of acquisition! 

In vivo PET/MRI images of a normal young C57BL/6 mouse using ¹⁸F radiolabelled 3: (a) whole body PET image showing distribution of ¹⁸F 30 minutes post injection (maximum intensity projection, mice in prone position); (b) PET/MRI fused image (coronal section, 0-15 minutes); (c) PET/MRI fused image (coronal section, 105-120 minutes); (d) MR image prior to the injection of NPs, and (e) MR image post the injection of NPs, showing a darkening contrast at lung and live area. Due to the unstable Al(OH)₃ shell, ¹⁸F-fluoride radioactivity was released from magnetic NPs 3 within 15 minutes and localised in bone.

The reconstruction features the TeraTomo algorithm's latest version which will be available for all our sites this autumn. In our opinion it is hard to get better bone images nowadays with PET for such a low injected activity than it’s featured in this article. Funnily enough noone intended to make bone images as this is a proof that the radiolabel went off from the nanoparticles and trapped in bones of the mouse. Remember, this is not a F-18 flouride bone scan! The ‘grainy’ PET image isn't the result of any regularization issue – this represents the real uneven flour uptake in the bones. You can notice the anatomical features of the knee joint – the patella, condyles of femur can be distinguished as well!

Read more about the integrated, automated small animal whole-body PET/MRI system.

[1] Cui, X. et al. Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging. Biomaterials doi:10.1016/j.biomaterials.2014.04.004 

Last month, in October a new review article titled Preclinical Imaging: an Essential Ally in Modern Biosciences on preclinical imaging technologies was published in the Molecular Diagnosis & Therapy journal. The journal provides insights into the latest molecular diagnostic and pharmacogenomic techniques and their use in personalized medicine.

Cunha, Lídia, Ildiko Horvath, Sara Ferreira, Joana Lemos, Pedro Costa, Domingos Vieira, Dániel S. Veres, et al. 2013. “Preclinical Imaging: An Essential Ally in Modern Biosciences.” Molecular Diagnosis & Therapy: 1–21. doi:10.1007/s40291-013-0062-3.

The find out that actually what is small-animal or preclinical imaging, P. Zanzonico from MSKCC has provided a good definition, stating that 'it constitutes a way of assessing biological structures and function in vivo by noninvasive means, allowing the collection of quantitative information, both in health and disease states' [1]. 

The main role of preclinical imaging is to deliver translational answers for serious health-related problems of the growing and aging world population. Small animal models have to represent a bridge between discoveries at the molecular level and clinical implementation in diagnostics or therapeutics. Small animal imaging is being used in a wide variety of lines of research, especially in infection, inflammation, oncology, cardiology, and neurosciences.

The article summarizes the general properties of diagnostic imaging modalities and reviews them one-by-one including Positron emission tomography (PET), Single photon emission computed tomography (SPECT), Optical imaging (OI), Computed tomography (CT), Magnetic resonance imaging (MRI) and Ultrasound (US) and their related  instrumentation of these modalities in small animal imaging. A separate and well detailed section is dedicated to the comparison of micro-SPECT and micro-PET. The general parameters are summarized in a large table listing imaging characteristics (spatial resolution, sensitivity, penetration depth, temporal resolution), related costs, probe types, major advantages, disadvantages and their application areas.  

There are inherent limitations to each imaging modality - this has brought commercial multi-modality systems 10+ years ago to the market.  Multimodal combination has enabled some of the most important limitations of each imaging modality to be overcome when used alone. The considerations are explained in the tenth sections of the article.
It's an honor to see multi-modality images of PET/MRI and SPECT/MRI acquired by our nanoScan imagers in the article.

A SPECT/MRI application was selected as the image of this blog post. The image shows transverse slices of SPECT and MRI images of a mouse brain. SPECT was acquired using a specific agent for cortical benzodiazepine receptors (¹²³I-NNC13-82431). The lack of anatomical information of SPECT acquisition is complemented with the information provided by MRI, in which the eyes, the olfactory bulbs and the first and second ventricles are shown. The multimodality SPECT/MRI image provides information about functional benzodiazepine receptors from SPECT allied to good soft tissue contrast from the MRI.

Abstract of the Article

Translational research is changing the practice of modern medicine and the way in which health problems are approached and solved. The use of small-animal models in basic and preclinical sciences is a major keystone for these kinds of research and development strategies, representing a bridge between discoveries at the molecular level and clinical implementation in diagnostics and/or therapeutics. The development of high-resolution in vivo imaging technologies provides a unique opportunity for studying disease in real time, in a quantitative way, at the molecular level, along with the ability to repeatedly and non-invasively monitor disease progression or response to treatment. The greatest advantages of preclinical imaging techniques include the reduction of biological variability and the opportunity to acquire, in continuity, an impressive amount of unique information (without interfering with the biological process under study) in distinct forms, repeated or modulated as needed, along with the substantial reduction in the number of animals required for a particular study, fully complying with 3R (Replacement, Reduction and Refinement) policies. The most suitable modalities for small-animal in vivo imaging applications are based on nuclear medicine techniques (essentially, positron emission tomography [PET] and single photon emission computed tomography [SPECT]), optical imaging (OI), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy imaging (MRSI), and ultrasound. Each modality has intrinsic advantages and limitations. More recently, aiming to overcome the inherent limitations of each imaging modality, multimodality devices designed to provide complementary information upon the pathophysiological process under study have gained popularity. The combination of high-resolution modalities, like micro-CT or micro-MRI, with highly sensitive techniques providing functional information, such as micro-PET or micro-SPECT, will continue to broaden the horizons of research in such key areas as infection, oncology, cardiology, and neurology, contributing not only to the understanding of the underlying mechanisms of disease, but also providing efficient and unique tools for evaluating new chemical entities and candidate drugs. The added value of small-animal imaging techniques has driven their increasing use by pharmaceutical companies, contract research organizations, and research institutions.

[1] Zanzonico P. Noninvasive imaging for supporting basic research. In: Kiessling F, Pichler BJ, editors. Small animal imaging—basics and practical guide. Heidelberg: Springer; 2011. p. 3–16. (Springer; Google Books)