Sir Peter MacCallum Department of Oncology - Research Publications
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ItemNo Preview AvailableDevelopment of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers(AMER CHEMICAL SOC, 2023-07-26)Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK2R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of 177Lu-labeled peptides ([177Lu]Lu-2b-4b) in comparison with the reference CCK2R-targeting peptide CP04 ([177Lu]Lu-1b). [177Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D7.4 (-4.09 to -4.55) with strong binding affinity to CCK2R (KD 0.097-1.61 nM), and relatively high protein binding (55.6-80.2%) and internalization (40-67%). Biodistribution studies of the novel 177Lu-labeled peptides in tumors (AR42J and A431-CCK2R) showed uptake one- to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [177Lu]Lu-2b-4b, making these compounds excellent candidates for theranostic applications against CCK2R-expressing tumors.
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ItemRadiolabelled Peptides: Optimal Candidates for Theranostic Application in Oncology(CSIRO PUBLISHING, 2022)Theranostics are drugs suitable for use in both diagnostic and therapeutic applications, and have played an important role in the advancement of modern nuclear medicine. This review explains key elements that are common to successful theranostics and highlights significant developments in the field, including our own. Specific focus is given to peptides and those features that make them most suitable for theranostic application, as well as some key radioisotopes owing to their favourable properties and high clinical utility. This report provides an overview of the techniques at the researcher’s disposal, how they have been applied to current clinically significant targets, and how they might be used and improved upon for future targets.
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ItemThe Protein Landscape of Mucinous Ovarian Cancer: Towards a Theranostic(MDPI, 2021-11)MOC is a rare histotype of epithelial ovarian cancer, and current management options are inadequate for the treatment of late stage or recurrent disease. A shift towards personalised medicines in ovarian cancer is being observed, with trials targeting specific molecular pathways, however, MOC lags due to its rarity. Theranostics is a rapidly evolving category of personalised medicine, encompassing both a diagnostic and therapeutic approach by recognising targets that are expressed highly in tumour tissue in order to deliver a therapeutic payload. The present review evaluates the protein landscape of MOC in recent immunohistochemical- and proteomic-based research, aiming to identify potential candidates for theranostic application. Fourteen proteins were selected based on cell membrane localisation: HER2, EGFR, FOLR1, RAC1, GPR158, CEACAM6, MUC16, PD-L1, NHE1, CEACAM5, MUC1, ACE2, GP2, and PTPRH. Optimal proteins to target using theranostic agents must exhibit high membrane expression on cancerous tissue with low expression on healthy tissue to afford improved disease outcomes with minimal off-target effects and toxicities. We provide guidelines to consider in the selection of a theranostic target for MOC and suggest future directions in evaluating the results of this review.
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ItemAutomated preparation of 2-[18F]fluoropropionate labeled peptides using a flexible, multi-stage synthesis platform (iPHASE Flexlab)(WILEY, 2018-02)Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi-step procedures, especially for fluorine-18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2-[18 F]fluoropropionate labeled RGD-peptides through use of the iPHASE Flexlab as an effective dual-stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD-peptides, [18 F]FP-GalactoRGD and [18 F]FP-c(RGDy(SO3 )K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD-peptides, [18 F]F-PRGD2 and [18 F]FP-E(RGDy(SO3 )K)2 , was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride.
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ItemA Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention(WILEY-V C H VERLAG GMBH, 2019-10-14)Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.
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ItemA Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper‐64 with High Tumor Uptake and Retention(Wiley, 2019-10-14)Abstract Molecules containing lysine‐ureido‐glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine‐ureido‐glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron‐emitting copper‐64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper‐67 variant.
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ItemGallium Fluoride Complexes with Acyclic Bispicolinic Ligands as Potential New Fluorine-18 Labelled Imaging Agents(WILEY-V C H VERLAG GMBH, 2020-09-22)The positron‐emitting radionuclide, fluorine‐18, is used to radiolabel molecules to develop tracers for diagnostic imaging with positron‐emission tomography. There is growing interest in the potential of using strong coordinate bonds between electropositive Ga(III) and electronegative fluoride (≈ 557 kJ/mol) to provide new methods of incorporating fluorine‐18 into molecules. The potential of gallium(III) complexes with acyclic pentadentate bispicolinic acid containing ligands (H2L1–3) to form ternary complexes with fluoride, [GaL1–3F] was investigated with a view to developing new methods for fluorine‐18 radiolabelling. A solid‐phase peptide synthesis approach was used to produce a bispicolinic acid chelator with a lysine residue. Characterisation of [GaL1X] (X = OH, Cl, F) by X‐ray crystallography revealed that L1 acted as dianionic N2O2 donor to the Ga(III) with the fifth site occupied by a monodentate anion (OH–, Cl– or F–). Despite its high stability in aqueous mixture and [D6]DMSO and the straightforward synthesis of [GaL1F], it was only possible to form the radioactive analogue [18F][GaL1F] in low radiochemical yields.
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Item4-Nitrophenyl activated esters are superior synthons for indirect radiofluorination of biomolecules(ROYAL SOC CHEMISTRY, 2020-08-01)Indirect radiolabelling has for a long time been the mainstay strategy for radiofluorination of biomolecules. Acylation of biomolecules through the use of an 18F-labelled activated ester is a standard method for indirect radiolabelling. However, the preparation of 18F-labelled activated esters is typically a complex and multistep procedure. Herein, we describe the use of 4-nitrophenyl (PNP) activated esters to rapidly prepare 18F-labelled acylation synthons in one step. Furthermore, we present a comparative study of PNP activated esters and the commonly utilised 2,3,5,6-tetrafluorphenyl (TFP) activated esters under direct radiofluorination conditions and demonstrate their relative acylation behaviour. We demonstrate the superiority of PNP esters under direct radiofluorination conditions with favourable acylation kinetics.
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ItemPET quantification of brain O-GlcNAcase with [18F]LSN3316612 in healthy human volunteers(SPRINGER, 2020-03-14)BACKGROUND: Previous studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research. METHODS: Kinetic evaluation of [18F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (VT) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of VT was assessed down to a 30-min scan time. An alternative quantification method for [18F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling. RESULTS: Brain uptake was generally high and could be quantified as VT with excellent identifiability using the two-tissue compartment model. [18F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of VT on the retest scan in nine of 10 volunteers. VT values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150-180 min) correlated strongly with regional VT values during test-retest conditions (R2 = 0.84), exhibiting similar reliability to VT (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18F]LSN3316612 PET was 20.5 ± 2.1 μSv/MBq, comparable to other 18F-labeled radioligands for brain imaging. CONCLUSIONS: [18F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of VT under retest conditions requires further investigation.
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ItemAutomated preparation of clinical grade [68Ga]Ga-DOTA-CP04, a cholecystokinin-2 receptor agonist, using iPHASE MultiSyn synthesis platform(SPRINGERNATURE, 2019-08-23)BACKGROUND: Gallium-68 ([68Ga]Ga) labelled radiopharmaceuticals have become a valuable tool in clinical practice using Positron Emission Tomography (PET). These agents are typically produced on-site owing to the short half-life of [68Ga]Ga (68 min), which hinders distant transportation and often cannot comply with Good Manufacturing Practice (GMP) in hospital environments due to limited resources or infrastructure constraints. Moreover, full blown GMP production of radiopharmaceuticals under development can be prohibitively expensive. [68Ga]Ga-DOTA-CP04 is a promising peptide for imaging neuroendocrine tumors overexpressing the cholecyctokinin-2 receptor. Automation is an integral process in ensuring the radiopharmaceuticals produced under non-GMP conditions are of a uniform quality for routine clinical use. Herein, we describe the development of an automation platform, the iPHASE MultiSyn radiosynthesizer, to produce 68Ga-labelled DOTA-CP04 for routine clinical provision. RESULTS: The use of the MultiSyn module for 68Ga-labelling of DOTA-CP04 was investigated. [68Ga]Ga-DOTA-CP04, was reproducibly prepared in high (> 70%) decay-corrected yields. [68Ga]Ga-DOTA-CP04 passed all predetermined acceptance criteria for human injection. CONCLUSIONS: [68Ga]Ga-DOTA-CP04 was produced effectively using the MultiSyn module in a consistent and reproducible manner suitable for human injection.