theme 4 biomedical engineering and imaging 2019/20 · mesenchymal stem cells (hmsc) differentiation...
TRANSCRIPT
Theme 4
Biomedical Engineering
and Imaging
2019/20
2
Contents 1.4 The neonatal virtual brain: computational models of emerging connectivity using simultaneous EEG and MRI ........................................................................................................................................ 4 3.4 Diffusion and structural MR histology: new high-resolution MR imaging methodologies for quantitative mapping of cortical organisation during development ......................................................... 6 4.4 Unravelling the role of pericellular matrix mechanics in regulating stem cell fate in 3D .......... 7 5.4 Detection of bone marrow cancer using high sensitivity 7T MRI ......................................................... 8 7.4 ‘RAGE’ as an imaging biomarker in Alzheimer’s disease - Structure-driven development, radiosynthesis and evaluation of a positron emission tomography radiotracer towards the Receptor for Advanced Glycation Endproducts (RAGE). .............................................................................. 10 8.4 Development of siRNA-based therapeutics for intestinal delivery in inflammatory bowel disease using imaging ............................................................................................................................................... 11 9.4 Development of sideromycin derivatives as fluorescent probes for the imaging of Gram+/-ve bacterial infections .................................................................................................................................................... 12 10.4 Design of novel 18F molecular probes for positron emission tomography brain imaging of the cannabinoid-1 receptor .................................................................................................................................... 14 11.4 Using molecular imaging to identify early cardiotoxicity due to cancer chemotherapy ....... 16
3
Imaging and Biomedical Engineering
This theme focuses on the link between biomedical and physical sciences – particularly
physics, engineering and computational approaches. Clinical functional and molecular
imaging (MRI, PET, X-MR and PET-MR) is a major strength, along with
computational modelling and biomaterials (particularly in the Dental Institute).
Lead: Professor Phil Blower
When choosing a project from this catalogue in the funding section of the online
application form please enter: MRCDTP2019_Theme4
Deadline for application: Sunday 25th November 2018
Shortlisted candidates will be contacted in early January.
Interviews: 30th & 31st January 2019
The 2019/20 studentships will commence in September 2019.
For further Information or queries relating to the application process please contact mrc-
Projects listed in this catalogue are subject to amendments, candidates
invited to interview will have the opportunity to discuss projects in
further detail.
4
1.4 The neonatal virtual brain: computational models of emerging connectivity using simultaneous
EEG and MRI
Co-Supervisor 1A: Dr. Dafnis Batalle
School/Division & CAG: IoPPN, Forensic & Neurodevelopmental Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/en/persons/dafnis-batalle(594a5a66-51aa-
421c-8863-39c245d3d93c)/projects.html
Co-Supervisor 1B: Dr. Tomoki Arichi
School/Division & CAG: Biomedical Engineering & Imaging Sciences
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/en/persons/tomoki-arichi(eb157769-4047-
47d1-b47a-95731abf11fe).html
Project description:
State-of-the-art mapping of structural and functional brain connectivity can enable the first use of
computational models of brain connectivity in newborn infants. This emerging field uses mathematical models
of neuronal activity to couple MRI-derived measures of white-matter structure and correlated functional
activity (Figure). As neuronal activity is fast and MRI suffers from low temporal resolution, further model
refinement is possible through incorporating high temporal resolution electrophysiology (EEG). We expect that this will provide important insights into both the emergence of brain connectivity and the biological alterations which underpin neurodevelopmental impairments resulting from perinatal injury.
This project will apply computational modelling techniques to a unique neonatal dataset of simultaneously
acquired EEG and MRI. Building on existing models derived from adult data, the student will develop
computational algorithms to link structural connectivity (from diffusion MRI) and functional connectivity (from
fMRI and EEG). This will include exploring different approaches such as Hopf Bifurcation and dynamic mean
field models and the adaptations needed for neonatal data. They will then aim to identify imaging phenotypes
and altered model parameters associated with neurodevelopmental disorders such as autism spectrum disorder.
Objectives:
5
Year 1/3: Training in neuroimaging and modelling. Characterisation of structural/functional connectivity from
MRI and EEG.
Year 2/3: Development of computational models linking structure and function.
Year 3/3: Identify model characteristics as biomarkers of brain pathology.
The successful student will receive training in neuroimaging, computational modelling, and developmental
neuroscience through the supervisory team; the School’s research and educational program; and external
educational courses and conferences.
One representative publication from each co-supervisor:
[1] Batalle D, Hughes EJ, Zhang H, Tournier J-D, Tusor N, Aljabar P, Wali L, Alexander DC, Hajnal JV,
Nosarti C, Edwards AD, Counsell SJ; Early development of structural networks and the impact of prematurity
on brain connectivity; Neuroimage, 2017, 149, pp. 379-392
[2] Arichi T, Whitehead K, Barone G, Pressler R, Padormo F, Edwards AD, Fabrizi L. Localization of
spontaneous bursting neuronal activity in the preterm human brain with simultaneous EEG-fMRI. eLIFE 2017;
e27814
6
3.4 Diffusion and structural MR histology: new high-resolution MR imaging methodologies for
quantitative mapping of cortical organisation during development
Co-Supervisor 1A: Flavio Dell’Acqua
School/Division & CAG: Academic Psychiatry - Forensic and Neurodevelopmental Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://www.scopus.com/authid/detail.uri?authorId=24757840500
https://kclpure.kcl.ac.uk/portal/en/persons/flavio-dell-acqua(3de057d5-
4de7-43d9-a44a-70ff1aca7963).html
Co-Supervisor 1B: Marija-Magdalena Petrinovic
School/Division & CAG: Academic Psychiatry - Forensic and Neurodevelopmental Sciences
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/marija-magdalena.petrinovic.html
Project description:
The cortex is one of the most complex regions of the brain, characterized by an extraordinary diversity of cell
types, whose coordinated development and function underlie memory, cognition, language, and consciousness.
The formation of laminar and columnar organisation during development is a fundamental prerequisite for
proper cortical function. Decoding this organisation during development has been at the core of neuroscientists’
work for decades. While traditional histological techniques provided critical insights about cortical features they
are limited by their invasive nature, they are time consuming and provide only a 2D-type of information of a
small part of the brain. Opposingly, MRI techniques non-invasively provide 3D-whole-brain coverage, but not
the high spatial resolution required to visualise cortical organisation. Aim of this project is to develop new MRI
protocols that will enable the quantitative characterisation of the laminar and columnar organisation during
typical and atypical (e.g. neurodevelopmental disorders) development in rodents.
In this project, the student will have access to the state-of-the-art preclinical imaging facilities at KCL including
the new 9.4T MRI scanner, the Nikon Imaging Centre and wet labs. The student will develop, and validate
(e.g. histology, cell cultures) new MRI structural and diffusion histology methods and will combine them with
novel microstructure diffusion imaging techniques. The goal is to develop new ultra-high resolution structural
and diffusion imaging methods able to probe cortical features at near histological resolution to map cortical
development in rats. Year 1-the student will learn technical skills and begin to acquire MRI and histological
data. Year 2/3-data analysis and methods development. This multidisciplinary project provides an outstanding
array of skills and a potential to rapidly impact upon our understanding of cortical development and
organisation.
One representative publication from each co-supervisor:
[1] Catani, M., Dell’Acqua, F., Budisavljevic, S., Howells, H., Thiebaut De Schotten, M., Froudist-Walsh, S.,
Williams, S.C. (2018). Frontal networks in adults with autism spectrum disorder. Brain, 139(2).
[2] Horder, J.,* Petrinovic, M.M*., Mendez, M.A., Bruns, A., Takumi, T., Spooren, W., Barker, G.J.,
Künnecke, B., Murphy, D.G. (2018). Glutamate and GABA in autism spectrum disorder-a translational
magnetic resonance spectroscopy study in man and rodent models. Translational Psychiatry. 8(1).
7
4.4 Unravelling the role of pericellular matrix mechanics in regulating stem cell fate in 3D
Co-Supervisor 1A: Cecile Dreiss
School/Division & CAG: Cancer & Pharmaceutical Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://www.kcl.ac.uk/lsm/research/divisions/ips/about/people/dreiss/index.aspx
Co-Supervisor 1B: Eileen Gentleman
School/Division & CAG: Dental Institute/Centre for Craniofacial and Regenerative Biology
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/eileen.gentleman.html
Project description:
Many tissue engineering (TE) paradigms aim to replace diseased/damaged tissues by directing human
mesenchymal stem cells (hMSC) differentiation with soluble chemicals/growth factors; however, physical
factors such as stiffness also influence differentiation. Using modifiable 3D hydrogels, we recently discovered
that in addition to detecting stiffness, encapsulated hMSC also actively modify their pericellular matrix (PCM)
to direct their fate (Ferreira, Nature Communications), and that PCM-mediated differentiation is driven by
hMSC’s ability to sense the stiffness of their secreted PCM.
To understand how secreted PCM drives lineage specification, this PhD project will build on our established
modifiable hydrogels to examine how hMSC mechanically modify their surroundings. Using multiple particle
tracking microrheology (MPT), which images fluorescent beads in live cultures, this project will measure
pericellular stiffening/softening in situ as differentiation proceeds. We will then determine mechanistically if
PCM mechanics direct differentiation, and if specific secreted proteins mediate this process. This will involve
treating cells with cytoskeletal inhibitors, incorporating non-cell-mediated controlled softening/stiffening into
hydrogels, and using targeted RNAi, protein secretion inhibitors, and tethering of specific proteins to the
hydrogel.
This interdisciplinary project requires a motivated student with a background in either the biological or physical
sciences who is willing to cross the boundaries of stem cell biology, mechanics and biomaterials synthesis.
Skills training:
hMSC culture, live cell imaging, microrheology, hydrogel synthesis, peptide design/synthesis, molecular
biology techniques
Objectives:
Year 1: MPT on hMSC in hydrogels
Year 2: Design/synthesise softening/stiffening/protein-tethered hydrogels
Year 3: Mechanistic molecular understanding of PCM-driven fate.
One representative publication from each co-supervisor:
[1] Ferreira SA, Motwani MS, Faull PA, Seymour AJ, Yu TTL, Enayati M, Taheem DK, Kania EM,
Oommen OP, Ahmed T, Loaiza S, Parzych K, Dazzi F, Auner HW, Varghese OP, Festy F, Grigoriadis AE,
Snijders AP, Bozec L, Gentleman E (2018) “Bi-directional cell-pericellular matrix interactions direct stem cell
fate.” In Press, Nature Communications
[2] Serres-Gomez M, González-Gaitano G, Kaldybekov DB, Mansfield ED, Khutoryanskiy VV, Isasi JR,
Dreiss CA (2018) “Supramolecular hybrid structures and gels from host-guest interactions between -
cyclodextrin and PEGylated organosilica nanoparticles”, Langmuir, DOI: 10.1021/acs.langmuir.8b01744
8
5.4 Detection of bone marrow cancer using high sensitivity 7T MRI
Co-Supervisor 1A: Dr Shaihan Malik
School/Division & CAG: BMEIS
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/shaihan.malik.html
Co-Supervisor 1B: Professor Vicky Goh
School/Division & CAG: BMEIS, Imaging CAG
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/vicky.goh.html
Project description:
Magnetic Resonance Imaging (MRI) plays an important role in the management of cancer patients.
However, its sensitivity for detecting cancer is limited in some body areas e.g. lung, skeleton, by their
intrinsically low MRI signal. New ultrahigh field strength (7T) scanners can potentially achieve much higher
sensitivity and spatial resolution than existing technology. We hypothesise that for bone-marrow imaging this
improved sensitivity will detect a low burden of bone marrow cancer or metastases, changing patient
management at an earlier stage. At present 7T-MRI is routinely successful for brain but less successful for
body imaging. The much higher resonant frequency at 7T compared to 1.5T clinical scanners (300MHz vs
64MHz) leads to uneven propagation of radio-frequency magnetic fields into the body, resulting in unusable
images. Parallel transmission systems (PTx), adapting to each patient, can improve this in principle. However,
existing methods are not suited to clinical workflows; hence the lack of progress in 7T clinical body imaging.
In this project we aim to develop clinical quality T1, T2 and diffusion-weighted 7T-MRI sequences, focussing
on the pelvis and thoraco-lumbar spine as an exemplar. These regions are commonly affected by myeloma
and metastatic disease and a significant challenge for 7T-MRI because of the wide field-of-view. The project
requires a student with a physics/engineering background, who will develop MR pulse sequences and
patient-adaptive PTx methods (Years 1&2), test these on healthy volunteers, and subsequently on clinical
patients (Years 2&3). They will be trained in operating and programming MRI scanners, including using
experimental hardware.
One representative publication from each co-supervisor:
[1] Beqiri, A., Hoogduin, H., Sbrizzi, A., Hajnal, J. V. & Malik, S. J. Whole-brain 3D FLAIR at 7T using
direct signal control. Magn. Reson. Med. 1–13 (2018). doi:10.1002/mrm.27149
[2] Cook GJR, Azad G, Taylor B, Lee E, Morrison M, Hughes S, Morris S, Rudman S, Chowdhury S, Goh
V. Imaging αvβ3 integrin expression in skeletal metastases with 99m
Tc-maraciclatide Single-Photon Emission
Computed Tomography: detection and therapy response assessment. Eur J Nucl Med Mol Imaging.
2018;45(6):898-903.
9
6.4 Predicting Optimal Ablation Patterns for Atrial Fibrillation
Co-Supervisor 1A: Prof Steven Niederer
School/Division & CAG: Biomedical Engineering & Imaging Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/steven.niederer.html
Co-Supervisor 1B: Dr Martin Bishop
School/Division & CAG: Biomedical Engineering & Imaging Sciences
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/martin.bishop.html
Project description:
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over 1.1 million people in the UK
alone, and is associated with increased risk of stroke and death. With increasing AF duration, the atrial tissue
undergoes electrical and structural remodelling, wavefront propagation becomes chaotic, and catheter ablation
treatment has a lower success rate. Our recent clinical data suggest that - though appearing chaotic - AF
electrical wavefronts follow preferential pathways when analysed probabilistically over time. Identifying, and
mechanistically understanding, these pathways has the potential to inform treatment approaches. We propose
to use a combined signal processing, computational modelling and machine learning approach to identify these
patient-specific pathways, to investigate the electrical and structural factors underlying these conduction
patterns, and to predict optimal ablation approaches.
This project provides training in signal and image processing techniques (Dr Roney), computational modelling
(Prof Niederer) and machine learning algorithms, applied to the field of cardiac electrophysiology. In particular,
the project involves generating atrial biophysical models from imaging data, tuned to electrophysiology data, in
close collaboration with the clinical teams at GSTT. Large numbers of biophysical simulations will be run and
analysed to investigate the mechanisms underlying different conduction patterns and to simulate different
ablation approaches.
Objectives:
1. To use and develop signal processing algorithms for identifying wavefront paths in clinical data,
2. To model the effects of atrial fibrosis, fibres, anatomy and electrophysiology on conduction pathways,
3. To predict using network theory approaches the pattern of ablation lesions required to terminate AF.
One representative publication from each co-supervisor:
Roney, C. H., Cantwell, C. D., Bayer, J. D., Qureshi, N. A., Lim, P. B., Tweedy, J. H., Kanagaratnam, P.,
Peters, N. S., Vigmond, E. J., … Ng, F. S. (2017). Spatial Resolution Requirements for Accurate
Identification of Drivers of Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology, 10(5), e004899.
Corrado, C., Williams, S., Karim, R., Plank, G., O'Neill, M., & Niederer, S. (2018). A work flow to build
and validate patient specific left atrium electrophysiology models from catheter measurements. Medical image
analysis, 47, 153-163.
10
7.4 ‘RAGE’ as an imaging biomarker in Alzheimer’s disease - Structure-driven development,
radiosynthesis and evaluation of a positron emission tomography radiotracer towards the Receptor
for Advanced Glycation Endproducts (RAGE).
Co-Supervisor 1A: Antony Gee
School/Division & CAG: School of Biomedical Engineering and Imaging Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/antony.gee.html
Co-Supervisor 1B: Salvatore Bongarzone
School/Division & CAG: School of Biomedical Engineering and Imaging Sciences
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/salvatore.bongarzone.html
Project description:
The receptor for advanced glycation endproducts (RAGE) is a transmembrane immunoglobulin-like receptor
and consists of extracellular, transmembrane and cytoplasmic domains. The extracellular region binds several
endogenous ligands, such as advanced glycation endproducts, amyloid-beta (Aβ) peptides and oligomers. The
binding of neurotoxic Aβ species to RAGE mediates the pre-neurodegenerative inflammatory process, and
induces an overexpression of the receptor itself as shown in the brain of patients with advanced Alzheimer’s
disease (AD) compared to mild disease or healthy controls.
The aim of the project is to develop the first biomarker able to identify expression level and localization of
RAGE and evaluation in preclinical animal models.
Positron emission tomography (PET) provides a qualitative and quantitative method for non-invasive
evaluation of RAGE distribution using PET radiolabeled compounds. The student will combine computational
structure-based and ligand-based protocols to design a library of brain penetrant compounds targeting the
extracellular RAGE domain (1st Year). The student will perform the radiosynthesis of selected compounds
using short-lived PET radionuclides (carbon-11 and fluorine-18) and evaluate their affinity to bind RAGE using
wild type and AD animal brain tissues (2nd Year ). The absorption, distribution, metabolism and excretion of
the RAGE PET radiotracer will be characterized in preclinical healthy animal and its potential as diagnostic
tool towards RAGE will be determined in AD mouse models (final year).
One representative publication from each co-supervisor:
[1] Bongarzone S, Savickas V, Luzi F, Gee AD. Targeting the Receptor for Advanced Glycation
Endproducts (RAGE): A Medicinal Chemistry Perspective. J. Med. Chem. 2017, 60(17), 7213.
[2] S. Bongarzone, F. Luzi, V. Savickas, N. Singh, F. Turkheimer, A. D. Gee Development of a carbon-11
PET tracer for imaging the Receptor for Advanced Glycation Endproducts (RAGE) in Alzheimer’s disease. J.
Labelled. Comp. Radiopharm. 2017, 60 (S1), S541.
11
8.4 Development of siRNA-based therapeutics for intestinal delivery in inflammatory bowel
disease using imaging
Co-Supervisor 1A: Driton Vllasaliu
School/Division & CAG: School of Cancer and Pharmaceutical Science
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/driton.vllasaliu.html
Co-Supervisor 1B: Maya Thanou
School/Division & CAG: School of Cancer and Pharmaceutical Science
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/maya.thanou.html
Project description:
Inflammatory bowel disease (IBD) affects >300,000 people (UK) and accounts for substantial
healthcare/society costs (€4.6–5.6 bn/year in Europe). Non-biologic therapy fails to influence underlying
inflammation and disease course. Biologics have changed IBD management, but injection-mediated
administration has serious limitations of systemic toxicity and loss of therapeutic response.
Locally-delivered RNA interference has significant therapeutic potential in IBD, specifically downregulating
expression of disease-relevant proinflammatory cytokines. However, intestinal delivery of small interfering
RNAs (siRNAs, large/complex molecules) is challenging. This project will develop nanosystems for intestinal
delivery of TNFα siRNA. Transcytosis-targeting, intestinal mucosa-penetrating nanoparticles carrying TNFα
siRNA will be fabricated from FDA-approved material (poly(lactic acid/glycolic acid polymer). Systems will
be characterised for physicochemical properties, cytotoxicity, epithelial cell uptake/permeation and gene
silencing. Near-Infrared Fluorescence (NIRF) imaging will be used in rodent studies with labelled siRNA
nanoparticles to determine tissue distribution/fate. This multidisciplinary project combines nanomedicine,
novel tissue culture and imaging. The student should have a biomedical engineering, or pharmaceutical
background.
These siRNA nanoparticles have potential for translation into effective therapies for delivery to inflamed
intestinal tissue via colon-targeting capsules or endoscopic devices.
Objectives:
Year 1: Delivery system formulation/characterisation, siRNA stability testing.
Year 2: In vitro toxicity, uptake/permeation testing (Caco-2 model), optimisation of gene silencing (testing in
Raw 264.7 macrophages).
Year 3: In vitro uptake testing in IBD-derived human intestinal organoids. In vivo imaging in mice with
experimentally-developed IBD.
Year 3.5: Thesis writing.
One representative publication from each co-supervisor:
[1] Hashem L, Swedrowska M, Vllasaliu D. Intestinal uptake and transport of albumin nanoparticles:
potential for oral delivery. Nanomedicine 2018, 13, 1255-1265.
[2] Kolli S, Wong SP, Harbottle R, Thanou M, Miller AD. PH-triggered nanoparticle mediated delivery of
siRNA to liver cells in vitro and in vivo. Bioconjugate Chemistry 2013, 24, 314-332.
12
9.4 Development of sideromycin derivatives as fluorescent probes for the imaging of Gram+/-ve
bacterial infections
Co-Supervisor 1A: Daniele Castagnolo
School/Division & CAG: School of Cancer and Pharmaceutical Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/daniele.castagnolo.html
Co-Supervisor 1B: James Mason
School/Division & CAG: School of Cancer and Pharmaceutical Sciences
KCL/KHP Email: [email protected]
KCL/KHP Website:
https://www.kcl.ac.uk/lsm/research/divisions/ips/research/drugdiscov/staff/mason.aspx
Project description:
Albomycin and salmycin belongs to the class of sideromycin antibiotics. Structurally, albomycin consists of a
thioribosyl pyrimidine antibiotic linked to a siderophore carrier responsible for its active transport into Gram+ve
and Gram-ve bacteria. Inside bacterial cells, albomycin is cleaved off the Fe3+
carrier by peptidase N, encoded
by pepN. The antibiotic stays inside the cells, whereas the iron-free carrier is excreted. Salmycin is a
siderophore‐linked-aminoglycoside and it inhibits almost exclusively Gram+ve bacteria. Salmycin is cleaved
inside bacterial cells by Fe3+
-reductase.
This project aims to exploit sideromycins as templates for the synthesis of novel fluorescent probes for bacterial
imaging. The siderophore carriers of albmomycin and salmycin will be linked to appropriate fluorescent probes
(i.e. fluorescein, dansyl, benzofurazans) which will be actively carried inside the bacterial cells and released after
metabolic cleavage allowing the imaging of the microorganisms. The cleavage of salmycin by Fe3+
-reductase
activity will be further exploited to design a switchable siderophore-fluorescein
Figure 1.
In addition, the less selective siderophore carrier of albomycin will be synthetically modified in order to increase
its selectivity toward strains of Gram-ve bacteria (in partcular N. gonorrea and K. pneumoniae). The project will be
carried out in close collaboration with Public Health England, which will provide a panel of ESKAPE bacteria
for imaging and toxicity studies.
13
Skills Training:
This project is multidisciplinary and it offers a combination of expertise and skills ranging from synthetic organic
and inorganic chemistry, fluorescence spectroscopy, microscopy, imaging and microbiology
The project will build on existing methods to map and compare adult cortical organisation (Glasser, Coalson,
Robinson et al, Nature 2016; 536:171-8)
One representative publication from each co-supervisor:
[1] Sanjib Bhakta, Nicolò Scalacci, Arundhati Maitra, Alistair K. Brown, Saiprasad Dasugari, Dimitrios
Evangelopoulos, Timothy D. McHugh, Parisa N. Mortazavi, Alexander Twist, Elena Petricci, Fabrizio
Manetti, Daniele Castagnolo*, Design and synthesis of 1-((1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-
yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethyl-octa-2,6-dienyl)-
ethane-1,2-diamine (SQ109) pyrrole hybrid derivatives: discovery of potent anti-tubercular agents effective
against multi-drug resistant mycobacteria. J. Med. Chem. 2016, 59, 2780-2793.
[2] Kozlowska, J., Vermeer, L.S., Rogers, G.B., Rehnnuma, N., Amos, S-B.T.A., Koller, G., McArthur, M.,
Bruce, K.D. & Mason, A.J.* Combined systems approaches reveal highly plastic responses to antimicrobial
peptide challenge in Escherichia coli. PLoS Pathogens 2014 (10) e1004104.
14
10.4 Design of novel 18F molecular probes for positron emission tomography brain imaging of the
cannabinoid-1 receptor
Co-Supervisor 1A: Dr Vincenzo Abbate
School/Division & CAG: School of Population Health & Environmental Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/vincenzo.abbate.html
Co-Supervisor 1B: Professor Paul Dargan
School/Division & CAG: Faculty of Life Sciences and Medicine, KCL; Clinical Toxicology, Acute
Medicine, Guy’s and St Thomas’ NHS Foundation Trust
KCL/KHP Email: [email protected]
KCL/KHPWebsite: https://www.guysandstthomas.nhs.uk/our-services/consultant-
profiles/toxicology/paul-dargan.aspx
Project description:
The endocannabinoid system, and in particular Cannabinoid-1-receptors (CB1R), is involved in various
physiological processes including memory, mood, pain-sensation, and appetite. Human brain imaging of CB1R
via Positron Emission Tomography (PET) has the potential to provide non-invasive and quantitative
measurement for the in-vivo evaluation of the biology and pharmacology of CB1R in numerous conditions such
as obesity, mood disorders, and addiction.
Recently, cumyl-carboxamide synthetic cannabinoids have emerged as highly potent drugs of abuse. These
potent and selective CB1R agonists (EC50 0.43−12.3nM) will be employed as lead compounds for CB1R PET
tracer development in this interdisciplinary/translational project. We will prepare a library of 18F-labelled cumyl-
carboxamides and systematically evaluate them in vivo (see figure below) to identify the most promising CB1R
PET tracer to enable translation into patients with future studies to screen for novel CB1R agonists/antagonists
for the conditions described above.
Objectives:
Year one:
1. Synthesis and characterization of the nonradioactive and 18F-labelled cannabinoids.
Year two and three:
2. In vitro evaluation of 18
F-labelled cumyl-carboxamides including logD measurement, stability in
human serum, and binding affinity and selectivity to CB1R
18FforPETImaging
asyntheticcannabinoidreceptorligand
Tracerinjection
PETImaging
15
3. In vivo PET imaging, blocking study using the CBR1 antagonist rimonabant, metabolism study, ex
vivo biodistribution, and brain tissue radioautography of 18F-labelled cumyl-carboxamides
4. Planning for clinical translation of the new tracers; thesis writing up and preparation for publication
and conference presentation
Skills Training:
Organic synthesis; analytical chemistry; safetly handling radioactive material; 18F-labelling methods; personal
animal licence; biodistribution study; metabolite analysis; in vivo pharmacokinetics; PET imaging and data
analysis; planning for clinical translation of the new tracers.
One representative publication from each co-supervisor:
[1] The Ongoing Challenge Of Novel Psychoactive Drugs Of Abuse. Part I. Synthetic Cannabinoids
Abbate, V., Schwenk, M., Presley, B. & Uchiyama, N. 2018, PURE AND APPLIED CHEMISTRY.
[2] Human toxicity caused by indole and indazole carboxylate synthetic cannabinoid receptor agonists: From horizon scanning to
notification Clinical Chemistry Volume 64, Issue 2, February 2018, Pages 346-354, Hill, S.L., Dunn, M., Cano,
C., Harnor, S.J., Hardcastle, I.R., Grundlingh, J., Dargan, P.I., Wood, D.M., Tucker, S.f, Bartram, T.,
Thomas, S.H.L.
16
11.4 Using molecular imaging to identify early cardiotoxicity due to cancer chemotherapy
Co-Supervisor 1A: Dr Richard Southworth
School/Division & CAG: Biomedical Engineering & Imaging Sciences
KCL/KHP E-mail: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/richard.southworth.html
Co-Supervisor 1B: Dr Thomas R. Eykyn
School/Division & CAG: Biomedical Engineering and imaging sciences
KCL/KHP Email: [email protected]
KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/thomas.eykyn.html
Project description:
Na/K ATPase pump function is the subject of renewed interest in oncology not only as a potential novel imaging
target, but also as a potential therapeutic target. Cancer cells exhibit an enhanced glycolytic phenotype. The
Na+/K+ ATPase is highly dependent on glycolytically-derived ATP, but the relationship between altered
metabolism during tumorigenesis, Na+/K+ ATPase activity and pathology is not well understood.
82Rb is a short-lived positron emitting radioisotope (75sec) and a biochemical analogue of potassium. Its short
half-life permits multiple injections into the same subject over a relatively short time period to track disease
progression, or response to therapy. Being generator produced, it does not require access to a cyclotron, and
which greatly enhances its availability. The primary use to date has been as a myocardial perfusion agent. As a
congener for K+, its primary mode of transport into the cell is via the sodium potassium pump (Na+/K+ ATPase).
We have recently investigated the potential of 82Rb as an imaging agent for basic biomedical investigation of
Na/K ATPase activity in the isolated perfused rat heart, tracking the injection, retention, and washout of
radiotracers in response to a variety of drugs, including ouabain (a cardiotonic Na/K ATPase inhibitor) and
isoprenaline (a −adrenergic agonist). Isoprenaline increased 82Rb uptake by 30% whilst ouabain reduced
uptake by 10-15%. These experiments point towards the possibility to develop an imaging technique using 82Rb
to report directly on Na/K ATP pump function, providing a new tool for cancer imaging.
(a)
(b)
17
(c)
100 2000.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
time (s)
control
isoprenaline
ouabain
No
rma
lised
in
ten
sity
(d)
Figure. (a) the CardioGen-82 clinical generator. (b) Preclinical perfusion system at KCL for studying the
pharmacokinetics of radiolabelled tracers in the isolated perfused heart. (c) Normalised, decay corrected 82Rb traces
from the heart detector under control perfusion conditions (black), following -adronergic stimulation with
isoprenaline (red) and following NaK inhibition with ouabain (blue). (d) Clinical 82Rb scan of a colon cancer patient,
axial section from pelvic area (courtesy Groves UCLH).
One representative publication from each co-supervisor:
[1] 64
Cu-CTS: A Promising Radiopharmaceutical for the Identification of Low-Grade Cardiac Hypoxia by
PET. Medina RA et al. J Nucl Med 56(6):921-6 2015.
[2] Multiple quantum filtered 23
Na NMR in the Langendorff perfused mouse heart: Ratio of Triple/ Double
quantum filtered signals correlate with [Na]I, Eykyn TR et al. J Mol Cell Card 86:95-101 2015.