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: Dept of 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

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Alam IS (2015) Radiopharmaceuticals as probes to characterize tumour tissue. in European journal of nuclear medicine and molecular imaging

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Allott L (2019) An improved automated radiosynthesis of [ 18 F]FET-ßAG-TOCA in Reaction Chemistry & Engineering

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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

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Evans HL (2014) A bioorthogonal (68)Ga-labelling strategy for rapid in vivo imaging. in Chemical communications (Cambridge, England)

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Gallo J (2014) CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging. in Angewandte Chemie (International ed. in English)

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O'Connor JP (2017) Imaging biomarker roadmap for cancer studies. in Nature reviews. Clinical oncology

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Sharma R (2020) Monitoring Response to Transarterial Chemoembolization in Hepatocellular Carcinoma Using F-Fluorothymidine PET. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

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Sharma R (2019) Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours. in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

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Witney TH (2014) Preclinical evaluation of 3-18F-fluoro-2,2-dimethylpropionic acid as an imaging agent for tumor detection. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

 
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.