Project title: Fluorine-18 labeled MIBG analogues for theranostic applications

Description

Raffel will assess a new PET radiotracer ([18F]3F-PHPG) to see whether it can perform significantly better than current methods (e.g. MIBG) for finding adrenal NETs.

What question will the researchers try to answer?

Is [18F]3F-PHPG a superior radiotracer for PET scans in humans for the diagnosis and localization of NETs in the adrenal system?

Why is this important?

This new radiotracer [18F]3F-PHPG may offer multiple benefits over a similar agent, [123I]MIGB, developed 40 years ago. [18F]3F-PHPG offers same-day imaging and provides high-resolution images that may be better able to find NETs.

What will researchers do?

Raffel will evaluate the diagnostic performance of [18F]3F-PHPG in 24 patients with NETs. The PET images of [18F]3F-PHPG uptake will be directly compared with additional scans using [123I]MIBG or the recently approved PET radiopharmaceutical [68Ga]DOTA-TATE).

How might this improve the treatment of NETs?

Raffel will compare existing approaches with [18F]3F-PHPG to see how it might improve diagnosis and treatment planning for pheochromocytoma and paraganglioma. In addition, the agent may have the potential to predict radiation dose delivery in [131I]MIBG therapy of NETs.

What is the next step?

If the results of this study demonstrate that [18F]3F-PHPG consistently provides high-quality diagnostic PET images outperforming [123I]MIBG, these clinical data will be leveraged to explore the development of a new radiotherapeutic agent for improved treatment of NETs based on the phenethylguanidine structure.

Outcomes:

The goal of our study was to evaluate the diagnostic performance of 3-[18F]fluoro-para-hydroxyphenethylguanidine ([18F]3F-PHPG), a new imaging agent for detecting paraganglioma (PGL) and pheochromocytoma (PCC) tumors using positron emission tomography (PET). Thirty subjects had PET scans with [18F]3F-PHPG, including 12 with PCC, 9 with PGL, 5 with head-and-neck paraganglioma (HN-PGL), 1 with both PCC and PGL, 1 with an adrenal cortical adenoma (ACA), 1 with an adrenal cortical carcinoma (ACC) and 1 with unknown pathology.

Tumor uptake of [18F]3F-PHPG is driven by adrenergic transporters, proteins on cell surfaces that actively transport the agent into tumor cells. These include the norepinephrine transporter (NET) and the two types of vesicular monoamine transporters, VMAT1 and VMAT2. Immunohistochemistry (IHC) staining of resected tumor sections from subjects was performed to determine the tumor expression levels of NET, VMAT1 and VMAT2.

In 20 out of the 30 cases, prior PET scans with [68Ga]DOTATATE (trade name NetSpot) were available to compare with the [18F]3F-PHPG scans. [68Ga]DOTATATE binds to somatostatin type 2 receptors, with then internalizes into tumor cells. In 6 subjects, we obtained planar scintigraphy scans with the original imaging agent for PGL and PCC, [123I]metaiodobenzylguanidine ([123I]MIBG), which is also substrate of NET and VMAT transporters.

In subjects with PGL and/or PCC, results with [18F]3F-PHPG were excellent, providing high quality images of tumors and metastases 90 min after tracer injection. In PGL and PCC subjects with comparison [68Ga]DOTATATE scans, findings were very similar for the two agents. In the five HN-PGL patients, two subjects had high [18F]3F-PHPG uptake, while the others had low uptake. This may be due to the highly variable expression of adrenergic transporters in this group of PGL patients. In two cases, suspected PCC tumors were later found to be either ACA or ACC after surgical resection. In these cases, the [18F]3F-PHPG scans were negative while the prior [68Ga]DOTATATE scans were positive. Thus, [18F]3F-PHPG had correctly shown that these were not adrenergic tumors like PGL or PCC.

In cases where [123I]MIBG scans were available, [18F]3F-PHPG was able to detect all lesions seen in the [123I]MIBG images, plus many smaller lesions that are hard to see in the noisy planar images. [18F]3F-PHPG also offers a practical advantage over [123I]MIBG for patients, by allowing same day imaging, while [123I]MIBG requires that the patient to come back to the clinic one day later for imaging.

We performed tumor immunohistochemistry studies in 24 subjects scanned with [18F]3F-PHPG. These will soon be interpreted by pathologists in our Research Pathology Core. These data will be evaluated for correlation of tumor uptake levels of [18F]3F-PHPG with the tumor expression levels of NET and VMAT transporters.

In summary, our findings show that in most cases of PGL and PCC, [18F]3F-PHPG typically provides comparable results with [68Ga]DOTATATE scans. However, [18F]3F-PHPG is more specific to neuroendocrine tumors that express the adrenergic transporters NET and VMAT. Thus results of both scans could aid physicians in making the correct diagnosis in challenging cases. Also, [18F]3F-PHPG shares many of the strengths of [123I]MIBG in detecting adrenergic neuroendocrine tumors, but with the advantages of same day imaging and the higher spatial resolution and tumor-to-background contrast provided by PET imaging over planar scintigraphy.

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