In this report, a simple and efficient process to achieve fluorine-18-labeled 1,2,3-triazole is reported. The heteroaromatic radiofluorination was successfully achieved through an iodine–fluorine-18 ...exchange in an aqueous medium requiring only trace amounts of base and no azeotropic drying of fluorine-18. This methodology was optimized on a model reaction and further validated on multiple 1,2,3-triazole substrates with 18–60% radiochemical conversions. Using this strategy—the radiosynthesis of a triazole-based thiamin analogue—a potential positron emission tomography (PET) probe for imaging thiamin-dependent enzymes was synthesized with 10–16% isolated radiochemical yield (RCY) in 40 min (uncorrected, n > 5).
Objective:
The goal is to evaluate avelumab, an anti-PD-L1 monoclonal immunoglobulin G antibody labeled with zirconium-89 in human PD-L1-expressing cancer cells and mouse xenografts for clinical ...translation.
Methods:
89ZrZr-DFO-PD-L1 monoclonal antibody (mAb) was synthesized using avelumab conjugated to desferrioxamine. In vitro binding studies and biodistribution studies were performed with PD-L1+MDA-MB231 cells and MDA-MB231 xenograft mouse models, respectively. Biodistributions were determined at 1, 2, 3, 5, and 7 days post coinjection of 89ZrZr-DFO-PD-L1 mAb without or with unlabeled avelumab (10, 20, 40, and 400 µg).
Results:
89ZrZr-DFO-PD-L1 mAb exhibited high affinity (Kd ∼ 0.3 nM) and detected moderate PD-L1 expression levels in MDA-MB231 cells. The spleen and lymph nodes exhibited the highest 89ZrZr-DFO-PD-L1 mAb uptakes in all time points, while MDA-MB231 tumor uptakes were lower but highly retained. In the unlabeled avelumab dose escalation studies, spleen tissue–muscle ratios decreased in a dose-dependent manner indicating specific 89ZrZr-DFO-PD-L1 mAb binding to PD-L1. In contrast, lymph node and tumor tissue–muscle ratios increased 4- to 5-fold at 20 and 40 µg avelumab doses.
Conclusions:
89ZrZr-DFO-PD-L1 mAb exhibited specific and high affinity for PD-L1 in vitro and had target tissue uptakes correlating with PD-L1 expression levels in vivo. 89ZrZr-DFO-PD-L1 mAb uptake in PD-L1+tumors increased with escalating doses of avelumab.
Favipiravir (T705; 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a pyrazine analog that has demonstrated potent antiviral activity against a broad spectrum of viruses in multiple in vivo disease ...models. To better understand the compounds anti-viral activity, assessment of the drug's biodistribution and kinetics in vivo may lend insight into how best to evaluate the compound efficacy preclinically and to contribute to the design of clinical studies to take into account the compound's pharmacokinetic distribution and kinetics. In the current study, a method for synthesis of
Ffavipiravir was developed and the biodistribution in mice naïve to and pre-dosed with favipiravir was assessed by PET and gamma counting of tissue samples. Fluorine-18 labeling of favipiravir was achieved in a one-pot, two-step synthesis using a commercially available precursor, methyl-5-chloroisoxazolo4,5-bpyrazine-3-carboxylate, with an overall radiochemical yield of 15-24%, a molar activity of 37-74 GBq/µmol in a 70 minute synthesis time.
Ffavipiravir tissue uptake and distribution was similar in naïve and pre-dosed mice; however, in the pre-dosed animals plasma clearance was more rapid and tissue clearance appeared to be prolonged. In conclusion, application of PET to the evaluation of favipiravir has demonstrated the importance of dosing regimen on the distribution and tissue uptake and clearance of the molecule. Favipiravir is cleared through the kidney as previously reported but the liver and intestinal excretion may also play an important role in compound elimination. Measurement of the tissue uptake of favipiravir as determined by PET may be a more important indicator of a compound's potential efficacy than purely monitoring plasma parameters such as viremia and drug levels.
The use of radiolabeled glucose for PET imaging resulted in the most commonly used tracer in the clinic, 2-deoxy-2-
Ffluoroglucose (FDG). More recently, other radiolabeled sugars have been reported ...for various applications, including imaging tumors and infections. Therefore, in this study, we developed a series of fluorine-18-labeled L-rhamnose derivatives as potential PET tracers of various fungal and bacterial strains. Acetyl-protected triflate precursors of rhamnose were prepared and radiolabeled with fluorine-18 followed by hydrolysis to produce L-deoxy
Ffluororhamnose. The overall radiochemical yield was 7-27% in a 90 min synthesis time with a radiochemical purity of 95%. In vivo biodistribution of the ligands using PET imaging showed that 2-deoxy-2-
Ffluoro-L-rhamnose is stable for at least up to 60 min in mice and eliminated via renal clearance. The tracer also exhibited minimal tissue or skeletal uptake in healthy mice resulting in a low background signal.
Desferrioxamine B (DFO) is the clinical standard chelator for preparing zirconium-89 labeled antibodies. In the current study, the stabilities of a zirconium-89 labeled panitumumab (PAN; Vectibix
) ...with three different chelators (DFO, DFO*, and DOTA) were compared. PAN is an anti-HER1/EGFR monoclonal antibody approved by the FDA for the treatment of HER1-expressing colorectal cancers and was used as the model antibody for this study. DFO/DFO* conjugates of PAN were directly radiolabeled with zirconium-89 at room temperature to produce
ZrZr-DFO/DFO*-PAN conjugates following a well-established procedure. A zirconium-89 labeled DOTA-PAN conjugate was prepared by an indirect radiolabeling method. A cyclooctyne-linked DOTA chelator (BCN-DOTA-GA) was first radiolabeled with zirconium-89 at 90 °C under a two-step basic pH adjustment method followed by conjugation with PAN-tetrazene at 37 °C to produce a labeled conjugate, BCN-
ZrZr-DOTA-GA-PAN. High reproducibility of the radiolabeling was observed via this two-step basic pH adjustment. The overall radiochemical yield was 40-50% (n = 12, decay uncorrected) with a radiochemical purity of >95% in 2 h synthesis time. All three conjugates were stable in whole human serum for up to 7 days at 37 °C. The kinetic inertness of the conjugates was assessed against the EDTA challenge. BCN-
ZrZr-DOTA-GA-PAN exhibited excellent inertness followed by
ZrZr-DFO*-PAN.
ZrZr-DFO-PAN displayed the lowest level of inertness.
Prostate-specific membrane antigen (PSMA) is present in high amounts in salivary glands, but it is unclear whether labeled binders of PSMA are excreted in the saliva.
Ten patients with prostate ...cancer underwent whole-body
FDCFPyL PET/CT (NCT03181867), and saliva samples were collected between 0-120 minutes post-injection.
FDCFPyL salivary excretion was measured over 120 minutes and expressed as %ID/g. Protein-associated binding was estimated by the percentage of
FDCFPyL versus parent radiotracer.
All PET scans of 10 patients (69 ± 8 years) with histologically confirmed prostate cancer (PSA= 2.4 ± 2.4, and Gleason Grade = 6-9) showed high uptake of
F-DCFPyL in salivary glands while 8 patients demonstrated high uptake in the saliva at 45 minutes. The intact
F-DCFPyL (98%) was also confirmed in the saliva samples at 120 min with increasing salivary radioactivity between 30-120 min.
Systemically injected
FDCFPyL shows salivary gland uptake, an increasing amount of which is secreted in saliva over time and is not maximized by 120 minutes post-injection. Although probably insignificant for diagnostic studies, patients undergoing PSMA-targeted therapies should be aware of radioactivity in saliva.
Pincer-type ligands are believed to be very robust scaffolds that can support multifarious functionalities as well as highly reactive metal motifs applied in organometallic chemistry, especially in ...the realm of catalysis. In this paper, we describe the redox and, therefore, noninnocent behavior of a PNP (PNP- = N2-P(CHMe2)2-4-methylphenyl2) pincer ancillary bound to nickel. A combination of structural, spectroscopic, and theoretical techniques suggests that this type of framework can house an electron hole when coordinated to Ni(II).
Abstract
Background
Several new generation CDK4/6 inhibitors have been developed and approved for breast cancer therapy in combination with endocrine therapeutics. Application of these inhibitors ...either alone or in combination in other solid tumors has been proposed, but no imaging biomarkers of response have been reported in non-breast cancer animal models. The purpose of this study was to evaluate 3'-
18
Ffluoro-3'-deoxythymidine (
18
FFLT) Positron Emission Tomography (PET) as in vivo biomarker of response to palbociclib in a non-breast cancer model.
Methods
Twenty-four NSG mice bearing patient derived xenografts (PDX) of a well-characterized bladder tumor were randomized into 4 treatment groups: vehicle (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle. Tumor uptake of
18
FFLT was determined by micro-PET/CT at baseline, 3 days, and 9 days post initiation of therapy. Following the second cycle of therapy, the mice were maintained until their tumors reached a size requiring humane termination.
Results
18
FFLT uptake decreased significantly in the palbociclib and combination arms (p = 0.0423 and 0.0106 respectively at day 3 and 0.0012 and 0.0031 at day 9) with stable tumor volume. In the temozolomide arm
18
FFLT uptake increased with day 9 uptake significantly different than baseline (p = 0.0418) and progressive tumor growth was observed during the treatment phase. All groups exhibited progressive disease after day 22, 10 days following cessation of therapy.
Conclusion
Significant decreases in
18
FFLT uptake as early as three days post initiation of therapy with palbociclib, alone or in combination with temozolomide, in this bladder cancer model correlates with an absence of tumor growth during therapy that persists until day 18 for the palbociclib group and day 22 for the combination group (6 days and 10 days) following cessation of therapy. These results support early modulation of
18
FFLT as an in vivo biomarker predictive of palbociclib therapy response in a non-breast cancer model.
There is current need for new approaches to assess/measure organ-level immunoreactivity and ensuing dysfunction in systemic inflammatory response syndrome (SIRS) and sepsis, in order to protect or ...recover organ function. Using a rat model of systemic sterile inflammatory shock (intravenous LPS administration), we performed PET imaging with a translocator protein (TSPO) tracer,
18
FDPA-714, as a biomarker for reactive immunoreactive changes in the brain and peripheral organs.
In vivo
dynamic PET/CT scans showed increased
18
FDPA-714 binding in the brain, lungs, liver and bone marrow, 4 hours after LPS injection. Post-LPS mean standard uptake values (SUV
mean)
at equilibrium were significantly higher in those organs compared to baseline. Changes in spleen
18
FDPA-714 binding were variable but generally decreased after LPS. SUV
mean
values in all organs, except the spleen, positively correlated with several serum cytokines/chemokines.
In vitro
measures of TSPO expression and immunofluorescent staining validated the imaging results. Noninvasive molecular imaging with
18
FDPA-714 PET in a rat model of systemic sterile inflammatory shock, along with
in vitro
measures of TSPO expression, showed brain, liver and lung inflammation, spleen monocytic efflux/lymphocytic activation and suggested increased bone marrow hematopoiesis. TSPO PET imaging can potentially be used to quantify SIRS and sepsis-associated organ-level immunoreactivity and assess the effectiveness of therapeutic and preventative approaches for associated organ failures,
in vivo
.
Objective. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is overexpressed in various cancers which has led to the development of therapeutic anti-Siglec-15 monoconal antibodies ...(mAbs). In these preclinical studies, the therapeutic mAb, NC318 (antihuman/murine Siglec-15 mAb), was labeled with zirconium-89 and evaluated in human Siglec-15 expressing cancer cells and mouse xenografts for potential use as a clinical diagnostic imaging agent. Methods. Desferrioxamine-conjugated NC318 was radiolabeled with zirconium-89 to synthesize 89ZrZr-DFO-NC318. Cancer cell lines expressing variable Siglec-15 levels were used for in vitro cell binding studies and tumor xenograft mouse models for biodistributions. 89ZrZr-DFO-NC318 biodistribution and PET imaging studies to determine tissue uptakes (tissue : muscle ratios, T : M) included pharmacokinetic evaluation in Siglec-15+tumor xenografts and immunocompetent mice, blocking with nonradioactive NC318 (20, 100, and 300 μg) and xenografts with low/negligible Siglec-15 expressing tumors. Results. 89ZrZr-DFO-NC318 exhibited high affinity (Kd~4 nM) for Siglec-15 and distinguished between moderate and negligible Siglec-15 expression levels in cancer cell lines. The highest 89ZrZr-DFO-NC318 uptakes occurred in the spleen and lymph nodes of the Siglec-15+tumor xenografts at all time points followed by Siglec-15+tumor uptake which was lower although highly retained. In immunocompetent mice, the spleen and lymph nodes exhibited lower uptakes indicating that the athymic xenografts had increased Siglec-15+ immune cells. Specific 89ZrZr-DFO-NC318 binding to Siglec-15 was proven with NC318 blocking studies in which dose-dependent decreases in Siglec-15+tumor T : Ms were observed. Higher than expected, tumor T : Ms were seen in lower expressing tumors likely due to the contribution of murine Siglec-15+ immune cells in the tumor microenvironment as confirmed by immunohistochemistry. Siglec-15+tumors were identified on PET images whereas low/negligible expressing tumors showed lower uptakes. Conclusions. In vitro and in vivo 89ZrZr-DFO-NC318 uptakes correlated with Siglec-15 expression levels in target tissues. Despite uptake in immune cell subsets in the tumor microenvironment, these results suggest that clinical 89ZrZr-DFO-NC318 PET imaging may have value in selecting patients for Siglec-15-targeted therapies.
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