were/are employed by Clarity Pharmaceuticals, the licensee of the intellectual property for SarTATE. C. M. Jeffery and P.S. Donnelly have potential financial interests in Clarity Pharmaceuticals. P. S. Donnelly is an inventor of intellectual property, in this area of research, which has been licensed from the University of Melbourne to Clarity Pharmaceuticals. Paul Donnelly serves on the Scientific Advisory Board of Clarity Pharmaceuticals. Unrelated to this project, Rodney Hicks has share options in Telix Radiopharmaceuticals that are held
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 therapyofprostate 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.T he bivalent agent, in which two targeting groups are tethered to as ingle copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake,l ow background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is apromising diagnostic for prostate cancer and could be used for prospective dosimetry for therapywith acopper-67 variant.
Alzheimer’s
disease is characterized by the presence of extracellular amyloid-β
plaques. Positron emission tomography (PET) imaging with tracers radiolabeled
with positron-emitting radionuclides that bind to amyloid-β
plaques can assist in the diagnosis of Alzheimer’s disease.
With the goal of designing new imaging agents radiolabeled with positron-emitting
copper-64 radionuclides that bind to amyloid-β plaques, a family
of bis(thiosemicarbazone) ligands with appended substituted stilbenyl
functional groups has been prepared. The ligands form charge-neutral
and stable complexes with copper(II). The new ligands can be radiolabeled
with copper-64 at room temperature. Two lead complexes were demonstrated
to bind to amyloid-β plaques present in post-mortem brain tissue
from subjects with clinically diagnosed Alzheimer’s disease
and crossed the blood-brain barrier in mice. The work presented here
provides strategies to prepare compounds with radionuclides of copper
that can be used for targeted brain PET imaging.
Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H 3 DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H 3 DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t 1/2 = 68 min) or zirconium-89 (t 1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.
Proteins adopt unique folded secondary
and tertiary structures
that are responsible for their remarkable biological properties. This
structural complexity is key in designing efficacious peptides that
can mimic the three-dimensional structure needed for biological function.
In this study, we employ different chemical strategies to induce and
stabilize a β-hairpin fold of peptides targeting cholecystokinin-2
receptors for theranostic application (combination of a targeted therapeutic
and a diagnostic companion). The newly developed peptides exhibited
enhanced folding capacity as demonstrated by circular dichroism (CD)
spectroscopy, ion-mobility spectrometry–mass spectrometry,
and two-dimensional (2D) NMR experiments. Enhanced folding characteristics
of the peptides led to increased biological potency, affording four
optimal Ga-68 labeled radiotracers ([68Ga]Ga-4b, [68Ga]Ga-11b–13b) targeting CCK-2R.
In particular, [68Ga]Ga-12b and [68Ga]Ga-13b presented improved metabolic stability, enhanced
cell internalization, and up to 6 fold increase in tumor uptake. These
peptides hold great promise as next-generation theranostic radiopharmaceuticals.
Identification of tumors which over-express Epidermal Growth Factor Receptor (EGFR) is important in selecting patients for anti-EGFR therapies. Enzymatic bioconjugation was used to introduce positron-emitting radionuclides (89Zr, 64Cu) into an...
Radiolabeled
derivatives of Tyr3-octreotide and Tyr3-octreotate,
synthetic analogues of the peptide hormone somatostatin,
can be used for positron emission tomography (PET) imaging of somatostatin
receptor expression in neuroendocrine tumors. In this work, a squaramide
ester derivative of desferrioxamine B (H3DFOSq) was used
attach either Tyr3-octreotide or Tyr3-octreotate
to the metal binding ligand to give H3DFOSq-TIDE and H3DFOSq-TATE. These new peptide-H3DFOSq conjugates
form stable complexes with either of the positron-emitting radionuclides
gallium-68 (t
1/2 = 68 min) or zirconium-89
(t
1/2 = 3.3 days). The new complexes were
evaluated in an AR42J xenograft model that has endogenous expression
of SSTR2. All four agents displayed good tumor uptake and produced
high-quality PET images. For both radionuclides, the complexes formed
with H3DFOSq-TATE performed better, with higher tumor uptake
and retention than the complexes formed with H3DFOSq-TIDE.
The versatile ligands presented here can be radiolabeled with either
gallium-68 or zirconium-89 at room temperature. The long radioactive
half-life of zirconium-89 makes distribution of pre-synthesized tracers
produced to certified standards feasible and could increase the number
of clinical centers that can perform diagnostic PET imaging of neuroendocrine
tumors.
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