The effect of novel aromatic heterocycle substituted aminamidine derivatives on Necator americanus.

BACKGROUND: The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control. OBJECTIVES: Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested. METHODS: The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses. RESULTS: Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis. CONCLUSIONS: Compound 3c is a novel and promising compound against N. americanus in vivo.

[18F]AlF-NOTA-PCP2: a novel PET/CT tracer for enhanced PD-L1 heterogeneity imaging and comparative analysis with [18F]AlF-NOTA-WL12 in glioblastoma xenografts.

PURPOSE: The unsatisfactory efficacy of PD-L1 antibodies in glioblastoma (GBM) is largely due to the temporal and spatial heterogeneity of PD-L1 expression. Molecular imaging can enhance understanding of the tumor immune microenvironment and guide immunotherapy. However, highly sensitive imaging agents capable of effectively visualizing PD-L1 heterogeneity are limited. This study introduces a novel PET tracer, offering improved imaging of PD-L1 heterogeneity in GBM xenografts, with a comparative analysis to [18F]AlF-NOTA-WL12. METHODS: [18F]AlF-NOTA-PCP2 was synthesized with high purity and its affinity for PD-L1 was characterized using surface plasmon resonance (SPR) and cell binding assays. Its specificity for PD-L1 was evaluated both in vitro using various cell lines and in vivo with GBM xenograft models in NOD/SCID mice. PET/CT imaging was conducted to evaluate the tracer's biodistribution, pharmacokinetics, and ability to quantify tumoral spatial heterogeneity of PD-L1 expression. A focused comparative analysis between [18F]AlF-NOTA-PCP2 and [18F]AlF-NOTA-WL12 was conducted, examining binding affinity, biodistribution, pharmacokinetics, and imaging effectiveness in GBM xenografts. Additionally, human radiation dosimetry estimates compared the safety profiles of both tracers. RESULTS: [18F]AlF-NOTA-PCP2 demonstrated high radiochemical purity (> 95%) and a strong affinity for PD-L1, comparable to [18F]AlF-NOTA-WL12. In vitro and in vivo studies confirmed its specificity for PD-L1, with increased uptake in PD-L1 expressing cells and tumors. Toxicological profiles indicated no significant abnormalities in serum biochemical indicators or major organ tissues. MicroPET/CT imaging showed [18F]AlF-NOTA-PCP2's effectiveness in visualizing PD-L1 expression levels and spatial heterogeneity in GBM xenografts. Comparative studies revealed [18F]AlF-NOTA-PCP2's improved pharmacokinetic properties, including higher tumor-to-blood ratios and lower nonspecific liver uptake, as well as reduced radiation exposure compared to [18F]AlF-NOTA-WL12. CONCLUSION: [18F]AlF-NOTA-PCP2 distinguishes itself as an exceptionally sensitive PET/CT tracer, adept at non-invasively and accurately quantifying PD-L1 expression and its spatial heterogeneity in tumors, especially in GBM. Its favorable pharmacokinetic properties, safety profile, and high affinity for PD-L1 highlight its potential for enhancing the precision of cancer immunotherapy and guiding individualized treatment strategies. While promising, its clinical translation, especially in brain imaging, necessitates further validation in clinical trials.

Synthesis and Evaluation of [18F]AlF-NOTA-c-DVAP: A Novel PET Probe for Imaging GRP78 in Cancer.

GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe's performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe's binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20-50 GBq/µmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of -3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.

Comparison of Human Tissue Gadolinium Retention and Elimination between Gadoteridol and Gadobenate.

Background Linear gadolinium-based contrast agents (GBCAs) are known to be retained at higher levels of gadolinium than macro-cyclic GBCAs. However, very little is known regarding their relative elimination rates and retained fraction of injected gadolinium. Purpose To quantify and compare gadolinium retention and elimination rates in human brain tissue, skin, and bone obtained from cadavers exposed to single-agent administration of either gadoteridol (macrocyclic GBCA) or gadobenate dimeglumine (linear GBCA). Materials and Methods Autopsy cases from August 2014 to July 2019 of patients exposed to a single type of GBCA, either gadoteridol or gadobenate dimeglumine, either single or multiple doses, were included. Gadolinium levels in the brain, skin, and bone were analyzed with inductively coupled plasma mass spectrometry. Linear regression was used to compare gadolinium retention between agents and estimate elimination rates of the retained gadolinium using the time between last injection and death. Results Twenty-eight cadavers with gadoteridol exposure and nine with gadobenate dimeglumine exposure were identified (22 men; age range, 19-83 years). The median gadolinium retention of gadobenate dimeglumine was 3.0-6.5 times higher than that of gadoteridol in the brain (P < .02), 4.4 times higher in bone (P = .002), and 2.9 times higher in skin (P = .05). Gadolinium retention in the globus pallidus (GP), dentate nucleus (DN), white matter (WM), bone, and skin decreased with time elapsed from last administration to death in both the gadobenate dimeglumine (GP: -3% per twofold increase in time, P = .69; DN: -2%, P = .83; WM: -20%, P = .01; bone: -22%, P = .07; skin: -47%, P < .001) and gadoteridol (GP: -17%, P = .11; DN: -16%, P = .15; WM: -30%, P < .001; bone: -11%, P = .16; skin: -24%, P = .01) groups (P values for elimination are compared with a null hypothesis of no elimination). Conclusion The linear agent gadobenate dimeglumine retains several-fold higher levels of gadolinium in the brain and bone compared with the macrocyclic agent gadoteridol. Nonzero elimination of retained gadolinium was detected in the white matter and skin for both agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Structure Activity Relationship of Key Heterocyclic Anti-Angiogenic Leads of Promising Potential in the Fight against Cancer.

Pathological angiogenesis is a hallmark of cancer; accordingly, a number of anticancer FDA-approved drugs act by inhibiting angiogenesis via different mechanisms. However, the development process of the most potent anti-angiogenics has met various hurdles including redundancy, multiplicity, and development of compensatory mechanisms by which blood vessels are remodeled. Moreover, identification of broad-spectrum anti-angiogenesis targets is proved to be required to enhance the efficacy of the anti-angiogenesis drugs. In this perspective, a proper understanding of the structure activity relationship (SAR) of the recent anti-angiogenics is required. Various anti-angiogenic classes have been developed over the years; among them, the heterocyclic organic compounds come to the fore as the most promising, with several drugs approved by the FDA. In this review, we discuss the structure-activity relationship of some promising potent heterocyclic anti-angiogenic leads. For each lead, a molecular modelling was also carried out in order to correlate its SAR and specificity to the active site. Furthermore, an in silico pharmacokinetics study for some representative leads was presented. Summarizing, new insights for further improvement for each lead have been reviewed.

Impaired Glymphatic Transport in Spontaneously Hypertensive Rats.

The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer's disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.SIGNIFICANCE STATEMENT The glymphatic system contributes to the removal of amyloid ß from the brain and is disrupted in Alzheimer's disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer's disease.

Quantification of cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and its metabolite regorafenib M2 in human plasma by UPLC-MS/MS.

A sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, i.e. olaparib and niraparib, and five tyrosine kinase inhibitors, i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib and regorafenib, plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope-labelled internal standards were used for each analyte. A simple protein precipitation method was performed with acetonitrile. The LC-MS/MS system consisted of an Acquity H-Class UPLC system, coupled to a Xevo TQ-S micro tandem mass spectrometer. The compounds were separated on a Waters CORTECS UPLC C18 column (2.1 × 50 mm, 1.6 µm particle size) and eluted with a gradient elution system. The ions were detected in the multiple reaction monitoring mode. The method was validated for cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and regorafenib M2 over the ranges 6-1000, 100-5000, 10-4000, 200-2000, 200-20,000, 5000-100,000, 500-10,000 and 500-10,000 µg/L, respectively. Within-day accuracy values for all analytes ranged from 86.8 to 115.0% with a precision of <10.4%. Between-day accuracy values ranged between 89.7 and 111.9% with a between-day precision of <7.4%. The developed method was successfully used for guiding therapy with therapeutic drug monitoring in cancer patients and clinical research programs in our laboratory.

Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft.

A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors, but fails to mobilize 33% of normal allogeneic sibling donors in 1 apheresis. We hypothesized that changing the route of administration of plerixafor from SC to IV may overcome the low stem cell yields and allow collection in 1 day. A phase 1 trial followed by a phase 2 efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0.32 mg/kg. The primary outcome of reducing the failure to collect ≥2 × 106 CD34+/kg recipient weight in 1 apheresis collection to ≤10% was not reached. The failure rate was 34%. Studies evaluating the stem cell phenotype and gene expression revealed a novel plasmacytoid dendritic cell precursor preferentially mobilized by plerixafor with high interferon-α producing ability. The observed cytomegalovirus (CMV) viremia rate for patients at risk was low (15%), as were the rates of acute grade 2-4 graft-versus-host disease (GVHD) (21%). Day 100 treatment related mortality was low (3%). In conclusion, plerixafor results in rapid stem cell mobilization regardless of route of administration and resulted in novel cellular composition of the graft and favorable recipient outcomes. These trials were registered at clinicaltrials.gov as #NCT00241358 and #NCT00914849.

DCE-MR imaging of orbital lesions: diagnostic performance of the tumor flow residence time τ calculated by a multi-compartmental pharmacokinetic tumor model based on individual factors.

BACKGROUND: Differentiating benign from malignant orbital lesions by imaging and clinical presentation can be challenging. PURPOSE: To differentiate benign from malignant orbital masses using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on tumor flow residence time τ calculated with the aid of a pharmacokinetic tumor model. MATERIAL AND METHODS: Sixty patients with orbital masses were investigated by 3-T MRI including dynamic sequences. The signal intensity-time curve after i.v. contrast medium administration within lesions was approximated by Gd-concentration profiles on the basis of model calculations where the tumor is embedded in a whole-body kinetic model. One output of the model was tumor flow residence time τ, defined as the ratio of the tumor volume and the tumor blood flow rate. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of τ. The results were compared with those of Ktrans, kep, ve, iAUC, and ADC. RESULTS: Thirty-one benign and 29 malignant orbital masses were identified (reference standard: histopathology, clinical characteristics). Mean τ was significantly longer for benign masses (94 ± 48 s) than for malignant masses (21 ± 19 s, P < 0.001). ROC analysis revealed the highest area under the curve (AUC = 0.94) for τ in orbital masses compared to standard methods. CONCLUSION: Tumor flow residence times τ of benign and malignant orbital masses are valuable in the diagnostic work-up of orbital tumors. Measures of diagnostic accuracy were superior for τ compared to ADC, Ktrans, ve, and iAUC.

Pharmacokinetics of tulathromycin in fetal sheep and pregnant ewes.

Macrolides are important antimicrobials frequently used in human and veterinary medicine in the treatment of pregnant women and pregnant livestock. They may be useful for the control of infectious ovine abortion, which has economic, animal health, and human health impacts. In this study, catheters were surgically placed in the fetal vasculature and amnion of pregnant ewes at 115 (±2) days of gestation. Ewes were given a single dose of 2.5 mg/kg tulathromycin subcutaneously, and drug concentrations were determined in fetal plasma, maternal plasma, and amniotic fluid at 4, 8, 12, 24, 36, 48, 72, 144, and 288 hr after drug administration. Pharmacokinetic parameters in maternal plasma were estimated using noncompartmental analysis and were similar to those previously reported in nonpregnant ewes. Tulathromycin was present in fetal plasma and amniotic fluid, indicating therapeutic potential for use against organisms in these compartments, though concentrations were lower than those in maternal plasma. Time-course of drug concentrations in the fetus was quite different than that in the ewe, with plasma concentrations reaching a plateau at 4 hr and remaining at this concentration for the remainder of the sampling period (288 hr), raising questions about how tulathromycin may be transported into or metabolized and eliminated by the fetus.

Effects of experimentally induced respiratory disease on the pharmacokinetics and tissue residues of tulathromycin in meat goats.

Tulathromycin is a macrolide antibiotic commonly used for the treatment of respiratory disease in food animal species including goats. Recent research in pigs has suggested that the presence of disease could alter the pharmacokinetics of tulathromycin in animals with respiratory disease. The objectives of this study were (a) compare the plasma pharmacokinetics of tulathromycin in healthy goats as well as goats with an induced respiratory disease; and (b) to compare the tissue residue concentrations of tulathromycin marker in both groups. For this trial, disease was induced with Pasteurella multocida. Following disease induction, tulathromycin was administered. Samples of plasma were collected at various time points up to 312 hr posttreatment, when study animals were euthanized and tissue samples were collected. For PK parameters in plasma, Vz (control: 28.7 ± 11.9 ml/kg; experimental: 57.8 ± 26.6 ml/kg) was significantly higher (p = 0.0454) in the experimental group than the control group, and nonsignificant differences were noted in other parameters. Among time points significantly lower plasma concentrations were noted in the experimental group at 168 hr (p = 0.023), 216 hr (p = 0.036), 264 hr (p = 0.0017), 288 hr (p = 0.0433), and 312 hr (p = 0.0486). None of the goats had tissue residues above the US bovine limit of 5 µg/g at the end of the study. No differences were observed between muscle, liver, or fat concentrations. A significantly lower concentration (p = 0.0095) was noted in the kidneys of experimental goats when compared to the control group. These results suggest that the effect of respiratory disease on the pharmacokinetics and tissue residues appear minimal after experimental P. multocida infection, however as evidenced by the disparity in Cmax , significant differences in plasma concentrations at terminal time points, as well as the differences in kidney concentrations, there is the potential for alterations in diseased versus clinical animals.

MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates.

Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer's disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 ± 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN. The volume of AAV2-BDNF (3 × 108 vg/µl) infusion linearly correlated with the number of BDNF labeled cells and the volume (mm3) of BDNF immunoreactivity in the entorhinal cortex. BDNF is normally trafficked to the hippocampus from the entorhinal cortex; in these experiments, we also found that BDNF immunoreactivity was elevated in the hippocampus following therapeutic BDNF vector delivery to the entorhinal cortex, achieving growth factor distribution through key memory circuits. These findings indicate that MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorhinal cortex and the hippocampus. These methods are adaptable to human clinical trials.

Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure.

Purpose To determine whether gadolinium remains in juvenile nonhuman primate tissue after maternal exposure to intravenous gadoteridol during pregnancy. Materials and Methods Gravid rhesus macaques and their offspring (n = 10) were maintained, as approved by the institutional animal care and utilization committee. They were prospectively studied as part of a pre-existing ongoing research protocol to evaluate the effects of maternal malnutrition on placental and fetal development. On gestational days 85 and 135, they underwent placental magnetic resonance imaging after intravenous gadoteridol administration. Amniocentesis was performed on day 135 prior to administration of the second dose of gadoteridol. After delivery, the offspring were followed for 7 months. Tissue samples from eight different organs and from blood were harvested from each juvenile macaque. Gadolinium levels were measured by using inductively coupled plasma mass spectrometry. Results Gadolinium concentration in the amniotic fluid was 0.028 × 10-5 %ID/g (percentage injected dose per gram of tissue) 50 days after administration of one gadoteridol dose. Gadolinium was most consistently detected in the femur (mean, 2.5 × 10-5 %ID/g; range, [0.81-4.1] × 10-5 %ID/g) and liver (mean, 0.15 × 10-5 %ID/g; range, [0-0.26] × 10-5 %ID/g). Levels were undetectable in the remaining sampled tissues, with the exception of one juvenile skin sample (0.07 × 10-5 %ID/g), one juvenile spleen sample (0.039 × 10-5 %ID/g), and one juvenile brain (0.095 × 10-5 %ID/g) and kidney (0.13 × 10-5 %ID/g) sample. Conclusion The presence of gadoteridol in the amniotic fluid after maternal injection enables confirmation that it crosses the placenta. Extremely low levels of gadolinium are found in juvenile macaque tissues after in utero exposure to two doses of gadoteridol, indicating that a very small amount of gadolinium persists after delivery. © RSNA, 2017.

Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T.

PURPOSE: We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. METHODS: We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated. RESULTS: In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna. CONCLUSION: Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med 79:1568-1578, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Positron Emission Tomography Imaging of Prostate Cancer with Ga-68-Labeled Gastrin-Releasing Peptide Receptor Agonist BBN7-14 and Antagonist RM26.

Radiolabeled bombesin (BBN) analogs have long been used for developing gastrin-releasing peptide receptor (GRPR) targeted imaging probes, and tracers with excellent in vivo performance including high tumor uptake, high contrast, and favorable pharmacokinetics are highly desired. In this study, we compared the 68Ga-labeled GRPR agonist (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, BBN7-14) and antagonist (d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) for the positron emission tomography (PET) imaging of prostate cancer. The in vitro stabilities, receptor binding, cell uptake, internalization, and efflux properties of the probes 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Aca-BBN7-14 and 68Ga-NOTA-poly(ethylene glycol)3 (PEG3)-RM26 were studied in PC-3 cells, and the in vivo GRPR targeting abilities and kinetics were investigated using PC-3 tumor xenografted mice. BBN7-14, PEG3-RM26, NOTA-Aca-BBN7-14, and NOTA-PEG3-RM26 showed similar binding affinity to GRPR. In PC-3 tumor-bearing mice, the tumor uptake of 68Ga-NOTA-PEG3-RM26 remained at around 3.00 percentage of injected dose per gram of tissue within 1 h after injection, in contrast with 68Ga-NOTA-Aca-BBN7-14, which demonstrated rapid elimination and high background signal. Additionally, the majority of the 68Ga-NOTA-PEG3-RM26 remained intact in mouse serum at 5 min after injection, while almost all of the 68Ga-NOTA-Aca-BBN7-14 was degraded under the same conditions, demonstrating more-favorable in vivo pharmacokinetic properties and metabolic stabilities of the antagonist probe relative to its agonist counterpart. Overall, the antagonistic GRPR targeted probe 68Ga-NOTA-PEG3-RM26 is a more-promising candidate than the agonist 68Ga-NOTA-Aca-BBN7-14 for the PET imaging of prostate cancer patients.

DOTA Functionalized Cross-Linked Small-Molecule Micelles for Theranostics Combining Magnetic Resonance Imaging and Chemotherapy.

Herein, a new theranostic nanoplatform was built by introducing DOTA on the surface of the cross-linked small molecular micelles. This nanoplatform consisted of three parts: (1) Hydrophobic alkyl chain functioned with alkenes as cross-linkable part to ensure the robust stability in vivo; (2) Hydrophilic DOTA for not only gadolinium ions complexion as MR imaging contrast agents but also platinum ions complexion as drug carriers; (3) Cisplatin as antitumor drug and MR imaging amplifier simultaneously. The metal loading content of the resulting Pt/Gd@DOTA-CSMs was up to 12 and 14 wt % for Gd(III) and Pt(II), respectively. The longitudinal relaxation rate of Gd@DOTA-CSMs (8.46 mM-1 s-1) was 2.6 times than that of the clinical Gd-DTPA (3.23 mM-1 s-1). When cisplatin was involved, not only great antitumor efficiency was achieved, but higher longitudinal relaxation rate of Pt/Gd@DOTA-CSMs (11.17 mM-1 s-1) was carried out due to the extension of rotational correlation time. The experiments of Balb/c mice bearing 4T1 xenograft indicated that Pt/Gd@DOTA-CSMs had better antitumor activity, lower side effect than clinically used cisplatin, and greater MR imaging than Gd-DTPA. All the results proved that the nanoplatform of DOTA-CSMs held remarkable potential in the field of therapeutics.

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats.

PURPOSE: To compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium-based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol. MATERIALS AND METHODS: Fifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28-day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: After 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05). CONCLUSION: Differences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:746-752.

Evaluation of Gadolinium Deposition in the Brain After MR Arthrography.

OBJECTIVE: Although significant investigation has been done into the deposition of gadolinium in the brains of patients receiving IV gadolinium, there is little research concerning nonintravenous uses of gadolinium, specifically in conjunction with musculoskeletal MR arthrography. Although small in volume, intraarticular administration is an off-label use of gadolinium, necessitating careful scrutiny for patient safety. Thus, we investigated the relationship between intraarticular gadolinium administration during MR arthrography and the presence of intracranial gadolinium deposition on subsequent brain MRI. MATERIALS AND METHODS: An institutional review board-approved retrospective study was performed of patients with no history of gadolinium exposure who underwent MR arthrography from 2006 to 2016 followed by an unenhanced brain MRI examination. ROIs were manually placed within bilateral dentate nuclei (DN), bilateral globus pallidi (GP), bilateral thalami, bilateral middle cerebral peduncles (MCP), and the central pons (CP) on T1-weighted sequences. The left and right ROIs were averaged, and ratios of signal intensity were calculated for DN/MCP, DN/CP, GP/MCP, GP/CP, thalamus/MCP, and thalamus/CP. Similar ROIs were placed and ratios calculated for age-matched control subjects who had a history of brain MRI but no prior gadolinium exposure. We used t testing to compare signal intensity ratios between patients and control subjects. RESULTS: A total of 31 patients met the inclusion criteria. We found no significant difference in signal intensity between patients and control subjects for DN/MCP (p = 0.40), DN/CP (p = 0.76), GP/MCP (p = 0.51), GP/CP (p = 0.86), thalamus/MCP (p = 0.93), and thalamus/CP (p = 0.30). CONCLUSION: No association was found between intraarticular gadolinium administration for MR arthrography and detectable gadolinium deposition within the brain.

Heterocycles: Versatile control elements in bioactive macrocycles.

The potential of macrocyclic peptides as therapeutics has garnered much attention over the last several years. Unlike their linear counterparts, macrocycles have higher resistance to enzymatic degradation and often display improved bioavailability. However, macrocycles are typically not lipophilic enough for cellular membrane penetration, which prevents them from interacting with intracellular targets. Methods to increase cellular permeability have involved the incorporation of bicyclic scaffolds, d-amino acids and N-methylation of amides. These modifications exert their effect through conformational control of macrocycles and have been well studied in the literature. In contrast, the structural consequences of heterocycle incorporation into macrocyclic rings has not been as exhaustively investigated. In this mini-review we discuss key examples in which heterocycles influence the conformational stability and other properties of macrocycles.

High-concentration iodinated contrast media for T1-weighted direct magnetic resonance arthrography.

AIM: To quantify in vitro the T1-weighted (T1W) expression of iodinated contrast media (CM), and to compare the in vivo performances of iodinated CM and gadolinium-based CM for T1W direct magnetic resonance imaging (MRI) arthrography. MATERIALS AND METHODS: An in vitro study on a 1.5 T MRI system was performed using Gd-DOTA, a mixture of iopromide and Gd-DOTA, and iopromide alone. The fat-suppressed (FS) T1W signal intensities were measured and analysed. In an in vivo study, 15 normal rabbits were used to compare the expression of iopromide (370 mg iodine/ml), and the mixture of iopromide and diluted Gd-DOTA. In nine of the 15 rabbits, extra-articular administrations of CM were performed to mimic the situation of CM leak. The rabbits were scanned on a 1.5 T MRI system, and the FS T1W sequence and an axial iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) T1W sequence were acquired. Signal intensities were measured and signal-to-noise ratios (SNR) were analysed. RESULTS: In the in vitro study, a higher SNR was noted in a higher concentration of iopromide, and the highest SNR of iopromide was 45.9% of that of Gd-DOTA. In the in vivo study, the iopromide and the mixture were well identified in all rabbits. The SNRs of the intra-articular and extra-articular iopromide and the mixture were significantly higher than the SNR of the muscles in the FS T1W images (all, p<0.01) and the IDEAL images (all, p<0.01). CONCLUSIONS: A high-concentration iodinated CM can provide good imaging quality for T1W direct MRI arthrography, and may be an alternative option in certain clinical situations.