Early detection of melanoma is essential, since a patient's prognosis with metastatic melanoma is poor. Previous studies showed that (111)In-DOTA-ReCCMSH(Arg(11)), a cyclic analogue of alpha-melanocyte stimulating hormone (alpha-MSH), exhibited high tumor concentration and rapid clearance from nontarget tissue. The goal of this current study was to label DOTA-ReCCMSH(Arg(11)) with beta(+)-emitting radionuclides, to determine if the high sensitivity of positron emission tomography (PET) imaging would aid in the detection of malignant melanoma. DOTA-ReCCMSH(Arg(11)) was labeled with (64)Cu and (86)Y. Biodistribution and small animal PET imaging were carried out in mice implanted with B16/F1 murine melanoma tumor and compared with data obtained in the same animal model with [(18)F]FDG. In both cases a subset of animals were co-injected with 20 microg of DOTA-ReCCMSH(Arg(11)) to determine if tumor concentration was receptor mediated. Tumor concentration for both the (86)Y- and (64)Cu-complexes reached a maximum at 30 min, while coadministering 20 microg of unlabeled complex reduced tumor uptake significantly. Nontarget organ concentration was considerably lower with (86)Y-DOTA-ReCCMSH(Arg(11)) than its (64)Cu analogue, except in the kidneys, where the (64)Cu complex had lower accumulation at all time points. Small animal PET images for both complexes showed the tumor could be visualized after 30 min, with the standardized uptake value (SUV) analysis following a similar trend as the biodistribution data. The data obtained suggests that DOTA-ReCCMSH(Arg(11)), when labeled with beta(+)-emitting radionuclides, has the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of PET.
Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The Al18F-labeling strategy involves chelation in aqueous medium of aluminum mono[18F]fluoride ({Al18F}2+) by a suitable chelator conjugated to a biomolecule. However, the need for elevated temperatures (100-120 °C) required for the chelation reaction limits its widespread use. Therefore, we designed a new restrained complexing agent (RESCA) for application of the AlF strategy at room temperature.Methods. The new chelator RESCA was conjugated to three relevant biologicals and the constructs were labeled with {Al18F}2+ to evaluate the generic applicability of the one-step Al18F-RESCA-method.Results. We successfully labeled human serum albumin with excellent radiochemical yields in less than 30 minutes and confirmed in vivo stability of the Al18F-labeled protein in rats. In addition, we efficiently labeled nanobodies targeting the Kupffer cell marker CRIg, and performed µPET studies in healthy and CRIg deficient mice to demonstrate that the proposed radiolabeling method does not affect the functional integrity of the protein. Finally, an affibody targeting HER2 (PEP04314) was labeled site-specifically, and the distribution profile of (±)-[18F]AlF(RESCA)-PEP04314 in a rhesus monkey was compared with that of [18F]AlF(NOTA)-PEP04314 using whole-body PET/CT.Conclusion. This generic radiolabeling method has the potential to be a kit-based fluorine-18 labeling strategy, and could have a large impact on PET radiochemical space, potentially enabling the development of many new fluorine-18 labeled protein-based radiotracers.
Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1-binding Affibody molecule NOTA-Z with F and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. The affinity of the PD-L1-binding Affibody ligand Z was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of F-AlF. In vivo studies were performed in PD-L1-positive, PD-L1-negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by γ-counting biodistribution. Immunohistochemical staining with an antibody specific for anti-PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. NOTA-Z was labeled, with a radiochemical yield of 15.1% ± 5.6%, radiochemical purity of 96.7% ± 2.0%, and specific activity of 14.6 ± 6.5 GBq/μmol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1-positive tumor, whereas the PD-L1-negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1-positive (percentage injected dose per gram [%ID/g] = 2.56 ± 0.33) and -negative (%ID/g = 0.32 ± 0.05) tumors ( = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.
This review will discuss the production and applications of positron-emitting radionuclides for use in Positron Emission Tomography (PET), with emphasis on radionuclides that can be produced onsite with a biomedical cyclotron. In PET the traditional radionuclides of choice are (11)C, (113)N, (15)O and (18)F and although they will be briefly discussed in this article, the emphasis of this review will be on 'non-standard' PET radionuclides that are generating increased interest by the medical research community.
Ex vivo autoradiography results using [⁶⁴Cu](Lys⁴⁰(DOTA)NH₂)Exendin-4 suggest that GLP-1R agonists based on Exendin-4 are attractive PET ligands for the in vivo determination of β-cell mass.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.