Project title: Efficient automated synthesis of silicon-[18F]fluoride acceptor (SiFA)-based neuroendocrine tumour imaging agents via “non-anhydrous, minimally basic” (NAMB) radio-fluorination chemistry.

Return To Search

Description

Dr. Inkster will develop state-of-the-art ¹⁸F radiolabeling methods designed to a) simplify the clinical production of peptide-based PET tracers targeting gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and b) facilitate the invention of novel ¹⁸F-labelled peptide hormone analogues useful for the diagnosis and localization of insulinomas.

What critical NET problem will you try to solve through your research?

The development of ¹⁸F-GEP-NET tracers has been impeded by synthetic challenges associated with the laborious radio-bioconjugation methods designed to indirectly radiolabel ligands of NET-associated peptide receptors under the automated conditions required for clinical use.

Why is this important?

Flourine-18 exhibits second-to-none PET imaging characteristics and is increasingly available due to worldwide demand for [¹⁸F]FDG. Thus, ¹⁸F-GEP-NET imaging agents that exhibit all the advantages of their radio-metalated (e.g. ¹¹¹In, ⁶⁸Ga) counterparts- namely, the straightforward, kit-like preparation of high molar activity radiopharmaceutical via automated synthesizers- would be highly desirable.

What will you do as part of this research project?

By merging two non-canonical ¹⁸F-labeling strategies- Silicon-[¹⁸F]fluoride Acceptor (SiFA) ¹⁹F-for-¹⁸F isotopic exchange and “non-anhydrous, minimally basic” (NAMB) ¹⁸F-fluorination chemistry, the Inkster lab plans to design and validate a single-step, automated radiosynthesis of a SiFA-modified Tyr³-octreotate derivative. These learnings with then be leveraged towards the design, synthesis and small animal PET assessment of novel SiFAylated peptides targeting the glucagon-like peptide 1 (GLP-1) receptor for insulinoma imaging.

How might your research improve the diagnosis and/or treatment of NETs?

This research seeks to generally improve and expand the clinical utility of high resolution ¹⁸F-PET imaging for NET diagnosis, staging and evaluation of therapeutic efforts. Regarding the treatment of insulinoma-induced hypoglycemia specifically, successful pre-operative imaging permits determination of tumor location on the pancreas and can guide the choice of full pancreatic resection vs partial resection vs tumor enucleation. The use of radio-metalated peptides for this application usually results in extensive renal uptake, which can complicate the delineation of nearby pancreatic lesions. The ¹⁸F-labelled GLP-1 receptor agonists developed in the Inkster lab are expected to exhibit reduced kidney retention, resulting in improved PET images.

What is your next step?

Establishment of a simple, reproducible and automated radiosynthetic protocol will permit preclinical assay of an expanded library of peptide sequences and pendant modifications. Highly promising GEP-NET tracers will be singled out for further translational development in collaboration with clinical researchers.

Outcomes:

Our lab developed a reliable way to make [18F]SiTATE, a “radiotracer” that helps doctors visialize neuroendocrine tumours (NETs) on 3D medical scans. Certain radiotracers can be used in conjunction with positron emission tomography (PET) scanners, allowing doctors to diagnose a patient, to see if the cancer has spread away from the original tumour (that is, to see how advanced it its), and to monitor response to treatments. All of this information can have a significant impact on cancer survival.

[18F]SiTATE is labelled with fluorine-18 (18F), a radioactive isotope that produces the clearest possible PET images but has a short half-life (110 min), so synthesis of 18F tracers much be done very quickly and efficiently. (A radioisotope’s “half-life” is the time it takes for half of a sample to decay.) These radioactive compounds are injected into patients, so they also must be made under sterile conditions; thus, clinical production of such 18F radiotracers much be made remotely, without being touched by human hands, using computer-controlled “Automated Synthesis Units” (ASUs) that reside inside lead-shield enclosures called hot cells.

Our group developed an ultra-efficient chemical method that is compatible with ASUs to produce very large amounts of [18F]SiTATE- enough to transport the tracer over large distances, to sites that have PET scanners but no means to make 18F. It also allows for the imaging of multiple patients with a single batch of [18F]SiTATE. This is something that is not possible with similar tracers labelled with gallium-68 (half-life = 68 min). The scientific paper that shares this technology was published in the journal Organic Process Research & Development in late 2025.

We have also been carrying out research designed to extended the same approach (dubbed “SiFAxNAMB”) two new 18F-labelled peptide tracers for imaging gastroenteropancreatic NETs (GEP-NETs- tumours of the gut and pancreas). [18F]Si OX EX and [18F]Si AM EX are both based on exendin-4 (a peptide originally identified in Gila monster saliva) and is designed to bind the glucagon like peptide-1 (GLP 1) cell surface receptor, which is often overexpressed in these cancers. These new 18F-labelled peptides much larger than [18F]SiTATE, which makes it harder to label efficiently. After extensive optimization, we obtained both in exceptional high radiochemical yields in an ASU, with good molar activities. (High molar activity ensures that 18F-tracer binds to its target receptors found on the cancer cells effectively.)

“Silicon-Fluoride Acceptor” (SiFA) radiolabelling methods represent a remarkable means to 18F-label a wide variety of tumour-targeting peptide sequences, but one of the reasons that there are not more compounds like [18F]SiTATE in development is that the SiFA prosthetic groups- the appendages that we attached to the peptide sequences that bind the fluorine-18- are difficult to make (synthesize). Thus, over the course of her PhD research, grad student Kevina Chavda has discovered simpler ways to make these 19F-bearing compounds, as well as an alternative type of precursor molecule that does not incorporate 18F via isotope exchange, but instead by OH-for-18F exchange.

Making these ‘tags’ easier to prepare motivates other centers to design, study and adopt new SiFA-bearing PET tracers. To this end, we made a prosthetic group and sent it to the lab of Prof. Eric Price (Canada Research Chair in Radiochemistry, Tier II), who will apply our labelling approach to PET tracers that target the gastrin releasing peptide (GRP) receptor, which is found on overexpressed in several neuroendocrine cancers, including small cell lung cancer, neuroendocrine tumours of the digestive tract, and neuroblastomas (hormone-producing, immature cancerous nerve cells).

Our lab intends to make our own new 18F-SiFA-peptide-based radiopharmaceuticals as well. Many NETs in their earlier stages expressed significant amount of somatostatin receptor 2 (SSTR2) on their surfaces, and targeting SSTR2 is the basis of which [18F]SiTATE and many other nuclear imaging agent and radiotherapeutics target NETs. However, (SSTR2) expression becomes downregulated in neuroendocrine cancer cells that have become abnormal and fast-growing. However, another cell surface receptor called CXCR4 behaves in the opposite fashion; it is upregulated in many aggressive and advanced neuroendocrine cancers. We plan to leverage the “SiFAxNAMB” labelling strategy- which we validated using NET/RF Pilot Grant funding- to 18F-label analogues of peptides that specifically target CXCR4, to see if this receptor might prove an effective way to selectively deliver radiation to these cancer types for both diagnosis and targeted radiotherapy.

« Back to all funded research projects