Compartmental analysis of dynamic nuclear medicine data: models and identifiability

Compartmental models based on tracer mass balance are extensively used in clinical and pre-clinical nuclear medicine in order to obtain quantitative information on tracer metabolism in the biological tissue. This paper is the first of a series of two that deal with the problem of tracer coefficient estimation via compartmental modelling in an inverse problem framework. Specifically, here we discuss the identifiability problem for a general n-dimension compartmental system and provide uniqueness results in the case of two-compartment and three-compartment compartmental models. The second paper will utilize this framework in order to show how non-linear regularization schemes can be applied to obtain numerical estimates of the tracer coefficients in the case of nuclear medicine data corresponding to brain, liver and kidney physiology

Somatostatin Receptor Scintigraphy in Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is a neuroendocrine tumor originating from the calcitonin‐secreting C cells. Surgery, consisting of a total thyroidectomy and an extensive lymph node dissection, is the only effective treatment in MTC; however, metastases are frequently found in the regional cervical lymph. The biochemical marker for MTC is calcitonin, and this is frequently used for the detection of persistent/residual/metastatic tumor. The value of 111In‐labeled somatostatin receptor scintigraphy (SRS) in patients with MTC is limited, with sensitivity ranging between 0 and 75%. Other scintigraphic imaging techniques such as 18F‐FDG PET, 18F‐DOPA PET, and PET imaging with 68Ga‐labeled DOTA peptides combined with CT imaging are upcoming. Treatment of patients with metastatic disease with the current available somatostatin analogues, octreotide and lanreotide, does not seem to have an effect on survival but may be considered to control flushing and diarrhea in some patients. Experience with peptide receptor radionuclide therapy is limited in this patient group and disappointing. New therapies in the treatment of metastatic MTC use target tyrosine kinase receptors inhibitors belonging to the same family group of proteins as RET

Other Radiopharmaceuticals for Imaging GEP‐NET

In GEP‐NETs, especially the catecholamine and serotonin biosynthetic pathways are upregulated. Therefore, increased biosynthesis of these specific amines in GEP‐NETs enables imaging with specific amine precursors. For the catecholamine pathway, 6‐18F ‐l‐3,4‐dihydroxyphenylalanine (18F‐DOPA) is available, while for the serotonin pathway, carbon‐11‐labeled 5‐hydroxy‐l‐tryptophan ([11C]‐5‐HTP) is available as tracer. 11C‐5‐HTP PET and 18F‐DOPA PET are excellent functional imaging techniques for evaluating patients with proven pancreatic islet cell tumors and carcinoids. For both tracers, the combination with CT further improves the detection rate of NET, which shows that performing PET scans with these tracers in PET/CT scanners is beneficial for patients.Since well‐differentiated GEP‐NETs generally have a low glucose metabolism, 18F‐fluorodexyglucose (18F‐FDG) PET scanning has limited value for the primary staging of patients with well‐differentiated GEP‐NETs. However, in patients with rapidly progressive disease, dedifferentiation of GEP‐NET tumors can lead to a higher glucose metabolism in tumor cells. In these patients, 18F‐FDG PET can be of benefit for tumor staging. Also, 18F‐FDG PET can be of value when other malignancies are suspected in patients with GEP‐NETs, since these patients experience a higher incidence of these malignancies compared to the general population.Nowadays, (GEP)‐NETs can also be imaged with 68Ga‐labeled analogues of somatostatin, which are also PET tracers. Advantages of 68Ga‐labeled somatostatin analogues are the relatively easy generator‐based synthesis and the possibility to evaluate whether peptide (somatostatin) receptor radionuclide therapy (PRRT) for NETs can be considered

Characterisation of targeted imaging and theranostic agents for cancer and fibrosis

Positron emission tomography (PET) imaging is a non-invasive modality that permits the characterisation of biological processes at the molecular level. Integrin αvβ6 and the chemokine receptor CXCR4 are important receptors in the pathogenesis of various cancers as well other diseases such as idiopathic pulmonary fibrosis (IPF) that may be exploited for the diagnosis, prognosis and assessment of therapeutic response. The gold-standard method for diagnosis of various cancers, such as breast, is immunohistochemistry (IHC), which suffers from a lack of a well-defined and reproducible cut-off value for tumour-positive or benign classification.The integrin αvβ6 is involved in various signalling pathways and it’s expression is generally very low in healthy tissues, and is greatly upregulated in various pathologies such as cancer and IPF, being linked to worse prognosis in pancreatic, head and neck, breast and ovarian cancers. Upregulation of αvβ6 during fibrosis or in tumours makes it an attractive target for a non-invasive imaging agent for the early detection of αvβ6 in cancer or IPF, monitoring of disease progression and the assessment of therapeutic response to existing or novel therapies. This thesis has evaluated αvβ6-targeted peptides for use as non-invasive PET imaging agents. [⁶⁸Ga]Ga-DO3A-JD2-RGD1 was selected as the lead peptide and demonstrated high affinity binding and high specificity for αvβ6 in competitive enzyme-linked immunosorbent assays, surface plasmon resonance and cellular binding assays in vitro as well as imaging and biodistribution studies in vivo using αvβ6+ cancer models, indicating its suitability for the detection of αvβ6 in cancer. Preliminary studies of [natLu]Lu-DO3A-JD2-RGD1 showed that chelation of lutetium-177 did not affect peptide binding to αvβ6, making it a promising potential peptide-receptor radionuclide therapy (PRRT) agent for αvβ6+ cancer.The chemokine receptor CXCR4 and its cognate ligand CXCL12 play a pivotal role in normal physiological processes. CXCR4 overexpression has been associated with over twenty types of human cancer with aggressive, invasive phenotypes, presenting a requirement for a non-invasive imaging agent for the detection of malignant sites including metastatic lesions. This thesis has evaluated the CXCR4-binding characteristics of novel tetraazamacrocycles [natCu]CuCB-bicyclam and [natCu]Cu2CB-bicyclam, synthesised by Archibald and colleagues, by surface plasmon resonance in a comparison study with the clinically used AMD3100. Both novel inhibitors were able to bind to CXCR4 with greater affinity than AMD3100, indicating their suitability for further validation as both PET imaging agents in CXCR4+ cancer detection and therapeutic agents in cancer and IPF

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)