(1) Background: 18FFlumazenil 1 (18FFMZ) is an established positron emission tomography (PET) radiotracer for the imaging of the gamma-aminobutyric acid (GABA) receptor subtype, GABAA in the brain. ...The production of 18FFMZ 1 for its clinical use has proven to be challenging, requiring harsh radiochemical conditions, while affording low radiochemical yields. Fully characterized, new methods for the improved production of 18FFMZ 1 are needed. (2) Methods: We investigate the use of late-stage copper-mediated radiofluorination of aryl stannanes to improve the production of 18FFMZ 1 that is suitable for clinical use. Mass spectrometry was used to identify the chemical by-products that were produced under the reaction conditions. (3) Results: The radiosynthesis of 18FFMZ 1 was fully automated using the iPhase FlexLab radiochemistry module, affording a 22.2 ± 2.7% (n = 5) decay-corrected yield after 80 min. 18FFMZ 1 was obtained with a high radiochemical purity (>98%) and molar activity (247.9 ± 25.9 GBq/µmol). (4) Conclusions: The copper-mediated radiofluorination of the stannyl precursor is an effective strategy for the production of clinically suitable 18FFMZ 1.
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.
A potential imaging and therapeutic agent for prostate cancer, with high tumor uptake and retention, has been prepared by tethering two lysine‐ureido‐glutamate peptides, which bind to prostate specific membrane antigen, to a single sarcophagine–copper complex.
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 (177LuLu-2b–4b) in comparison with the reference CCK2R-targeting peptide CP04 (177LuLu-1b). 177LuLu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D 7.4 (−4.09 to −4.55) with strong binding affinity to CCK2R (K D 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 177LuLu-2b–4b, making these compounds excellent candidates for theranostic applications against CCK2R-expressing tumors.
For over 40 years,
F-FDG has been the dominant PET tracer in neurology, cardiology, inflammatory diseases, and, most particularly, oncology. Combined with the ability to perform whole-body scanning,
...F-FDG has revolutionized the evaluation of cancer and has stifled the adoption of other tracers, except in situations where low avidity or high background activity limits diagnostic performance. The strength of
F-FDG has generally been its ability to detect disease in the absence of structural abnormality, thereby enhancing diagnostic sensitivity, but its simultaneous weakness has been a lack of specificity due to diverse pathologies with enhanced glycolysis. Radiotracers that leverage other hallmarks of cancer or specific cell-surface targets are gradually finding a niche in the diagnostic armamentarium. However, none have had sufficient sensitivity to realistically compete with
F-FDG for evaluation of the broad spectrum of malignancies. Perhaps, this situation is about to change with development of a class of tracers targeting fibroblast activation protein that have low uptake in almost all normal tissues but high uptake in most cancer types. In this review, the development and exciting preliminary clinical data relating to various fibroblast activation protein-specific small-molecule inhibitor tracers in oncology will be discussed along with potential nononcologic applications.
The synthesis of new bis(thiosemicarbazonato)copper(II) complexes featuring polyamine substituents via selective transamination reactions is presented. Polyamines of different lengths, with ...different ionizable substituent groups, were used to modify and adjust the hydrophilic/lipophilic balance of the copper complexes. The new analogues were radiolabeled with copper-64 and their lipophilicities estimated using distribution coefficients. The cell uptake of the new polyamine complexes was investigated with preliminary in vitro biological studies using a neuroblastoma cancer cell line. The in vivo biodistribution of three of the new analogues was investigated in vivo in mice using positron-emission tomography imaging, and one of the new complexes was compared to 64CuCu(atsm) in an A431 squamous cell carcinoma xenograft model. Modification of the copper complexes with various amine-containing functional groups alters the biodistribution of the complexes in mice. One complex, with a pendent (N,N-dimethylamino)ethane functional group, displayed tumor uptake similar to that of 64CuCu(atsm) but higher brain uptake, suggesting that this compound has the potential to be of use in the diagnostic brain imaging of tumors and neurodegenerative diseases.
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 (H3DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H3DFOSq 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 (68GaGa-4b, 68GaGa-11b–13b) targeting CCK-2R. In particular, 68GaGa-12b and 68GaGa-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.
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.
Peptides are ideal for theranostic development as they afford rapid target accumulation, fast clearance from background tissue, and exhibit good tissue penetration. Previously, we developed a novel ...series of peptides that presented discreet folding propensity leading to an optimal candidate
GaGa-DOTA-
(D-Glu
-Ala-Tyr-
MeGly-Trp-
MeNle-Asp-Nal-NH
) with 50 pM binding affinity against cholecystokinin-2 receptors (CCK
R). However, we were confronted with challenges of unfavorably high renal uptake.
A structure activity relationship study was undertaken of the lead theranostic candidate. Prudent structural modifications were made to the peptide scaffold to evaluate the contributions of specific
-terminal residues to the overall biological activity. Optimal candidates were then evaluated in nude mice bearing transfected A431-CCK
tumors, and their biodistribution was quantitated
.
We identified and confirmed that D-Glu
to D-Ala
substitution produced 2 optimal candidates,
GaGa-DOTA-
and
GaGa-DOTA-
. These radiopeptides presented with high target/background ratios, enhanced tumor retention, excellent metabolic stability in plasma and mice organ homogenates, and a 4-fold reduction in renal uptake, significantly outperforming their non-alanine counterparts.
Our study identified novel radiopharmaceutical candidates that target the CCK
R. Their high tumor uptake and reduced renal accumulation warrant clinical translation.
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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