MICA: DCS - Evaluation of [18F]fluoroethyl triazole labelled [Tyr3]Octreotate analogues for the imaging of neuroendocrine tumours
Lead Research Organisation:
Imperial College London
Department Name: Surgery and Cancer
Abstract
The incidence and prevalence of gastroenteropancreatic neuroendocrine tumours (NETs) has been increasing over the past three decades. Due to the high density of somatostatin receptors (SSTR), mainly SSTR2, on the cell surface of these tumours, imaging of tumours is possible. Existing technologies have poor sensitivity and so new methods are being explored. One potential area is the use of 18F-labelled tracers for Positron Emission Tomography (PET) scanning which are much more sensitive and specific to the tumours of interest than exisiting tracers and also have a reduced scanning time. Previous work by this group, under a Developmental Pathway Funding Scheme (DPFS) award, designed five structurally-related [18F]-fluoroethyltriazole-[Tyr3]octreotate analogues. Based on the findings of this work, one candidate compound ( [18F]-FET-betaAG-TOCA) was chosen as the lead compound to take forward into clinical development. We propose to develop [18F]-FET-betaAG-TOCA clinically via a 2 stage trial design. The initial study will assess the pharmacokinetics (PK), biodistribution and safety of the novel tracer employing 'whole body dynamic PET scanning'; of particular interest will be the optimal time for imaging. Using this information we will construct an appropriate protocol for 'whole body static PET scanning' in the subsequent study. We will then compare the diagnostic efficacy of [18F]-FET-betaAG-TOCA PET/CT to [68Ga]-DOTATATE PET/CT (a method currently used for NETs) in patients with a histological diagnosis of NET. These clinical studies will be used as the basis for future larger clinical trials and a Department of Health application to establish this tracer as the new clinical standard based on equivalent sensitivity and specificity but improved kinetics and handling, as well as ease of GMP manufacturing than the existing [68Ga]-DOTATATE PET/CT.
Technical Summary
The incidence and prevalence of gastroenteropancreatic neuroendocrine tumours (NETs) has been increasing over the past three decades. Due to the high density of somatostatin receptors (SSTR), mainly SSTR2, on the cell surface of these tumours, [111In]-DTPA-octreotide scintigraphy (SRS) has become an important part of clinical management. More recently, however, [68Ga] labelled octreotate analogues are being increasingly used because of their improved sensitivity and specificity (Gabriel et al., 2007). Fluorine-18 radiolabelled analogues with suitable PK would permit positron emission tomography (PET) with more rapid clinical protocols. Previous work by this group, under a Developmental Pathway Funding Scheme (DPFS) award, designed five structurally-related [18F]-fluoroethyltriazole-[Tyr3]octreotate analogues. Based on high binding affinity and low tumour-to-background noise ratio, within this series and also compared to other related F-18 and Ga-68 SSTR imaging agents, we selected [18F]-FET-betaAG-TOCA as the lead compound to take forward into clinical development. We propose to develop [18F]-FET-betaAG-TOCA clinically via a 2 stage trial design. The initial study will assess the pharmacokinetics (PK), biodistribution and safety of the novel tracer employing 'whole body dynamic PET scanning'; of particular interest will be the optimal time for imaging. Using this information we will construct an appropriate protocol for 'whole body static PET scanning' in the subsequent study. We will then compare the diagnostic efficacy of [18F]-FET-betaAG-TOCA PET/CT to [68Ga]-DOTATATE PET/CT in patients with a histological diagnosis of NET. These clinical studies will be used as the basis for future larger clinical trials and a Department of Health application to establish this tracer as the new clinical standard based on equivalent sensitivity and specificity but improved kinetics and handling, as well as ease of GMP manufacturing than the existing [68Ga]-DOTATATE PET/CT.
Planned Impact
Nuclear medicine physicians, oncologists, endocrinologists and other specialty areas involved in the management of NETs will benefit from a more readily available, accurate diagnostic and staging technique. This will assist with decision making regarding surgery, radiolabelled somatostatin therapy or other systemic agents. Ultimately, more accurate staging will benefit patients. Over the past six months, over sixty patients have been referred to the NET team at the Hammersmith Hospital alone making this tumour a significant problem that requires accurate diagnostic imaging.
Publications
Challapalli A
(2015)
3'-Deoxy-3'-¹8F-fluorothymidine positron emission tomography as an early predictor of disease progression in patients with advanced and metastatic pancreatic cancer.
in European journal of nuclear medicine and molecular imaging
Challapalli A
(2016)
Positron Emission Tomography Imaging of Tumor Cell Metabolism and Application to Therapy Response Monitoring.
in Frontiers in oncology
Corovic A
(2023)
Somatostatin Receptor PET/MR Imaging of Inflammation in Patients With Large Vessel Vasculitis and Atherosclerosis.
in Journal of the American College of Cardiology
Dubash SR
(2016)
Clinical Translation of a Click-Labeled 18F-Octreotate Radioligand for Imaging Neuroendocrine Tumors.
in Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Evans HL
(2014)
A bioorthogonal (68)Ga-labelling strategy for rapid in vivo imaging.
in Chemical communications (Cambridge, England)
Evans JS
(2022)
Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy.
in European journal of cancer (Oxford, England : 1990)
Gallo J
(2014)
CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging.
in Angewandte Chemie (International ed. in English)
Heinzmann K
(2016)
The relationship between endogenous thymidine concentrations and [(18)F]FLT uptake in a range of preclinical tumour models.
in EJNMMI research
Hopkins TG
(2016)
The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.
in Nucleic acids research
Description | Developmental Clinical Studies |
Amount | £768,583 (GBP) |
Funding ID | MR/J007986/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2013 |
End | 01/2016 |
Title | novel [18F]Fluoroethyltriazol-[Tyr3]Octreotate analogues |
Description | The DPFS grant allowed development of the new imaging compound and pre-clinical assessment to be completed. We have now applied for a DCS grant to allow clinical testing. |
Type | Diagnostic Tool - Imaging |
Current Stage Of Development | Refinement. Non-clinical |
Year Development Stage Completed | 2010 |
Development Status | Under active development/distribution |
Impact | Analogues developed resulted in a patent filing. First in Man study due to start end of 2012. |