Conventional uroradiology with excretory urography: a forgotten art?

Excretory urography (EU) had been the most frequently performed imaging modality for uroradiology in the past. With the advances in Ultrasonography, and development of cross-sectional urography with Computed tomography (CT) and Magnetic resonance Imaging (MRI), EU is now seldom performed. Consequently, there has been a decline of expertise in this technique. However, EU has multiple advantages such as dynamic nature, easy availability, low cost and radiation burden. These render it potentially very valuable in specific indications like congenital anomalies, urothelial lesions and urinary leaks. This review intends to emphasize the current day relevance of excretory urography, outline the key points of the technique, and describe the pearls and pitfalls of interpretation.

Synergistic Experimental and Computational Investigation of the Bioorthogonal Reactivity of Substituted Aryltetrazines

Tetrazines (Tz) have been applied as bioorthogonal agents for various biomedical applications including pretargeted imaging approaches. In radioimmunoimaging, pretargeting increases the target-to-background ratio while simultaneously reducing the radiation burden. We have recently reported a strategy to directly 18F-label highly reactive tetrazines based on a 3-(3-fluorophenyl)-Tz core structure. Herein, we report a kinetic study on this versatile scaffold. A library of 40 different tetrazines was prepared, fully characterized, and investigated with emphasis on second order rate constants for the reaction with trans-cyclooctene (TCO). Our results reveal the effects of various substitution patterns and moreover demonstrate the importance of measuring reactivities in the solvent of interest, as click rates in different solvents do not necessarily correlate well. In particular, we report that tetrazines modified in 2-position of the phenyl substituent show high intrinsic reactivity towards TCO, which is diminished in aqueous systems by unfavorable solvent effects. The obtained results enable the prediction of the bioorthogonal reactivity and thereby facilitate the development of the next-generation of substituted aryltetrazines for in vivo application.

Pre-procedural CT imaging aids neonatal PDA stenting for ductal-dependent pulmonary blood flow with reduction in overall procedural morbidity

Patent ductus arteriosus stenting for ductal-dependent pulmonary blood flow is a technically challenging neonatal procedure to maintain a stable pulmonary circulation. Pre-procedural computed tomography imaging aids in outlining ductal origin, insertion, size, course and curvature. Computed tomography imaging may add value to procedural outcomes and reduce overall procedural morbidity in neonatal patent ductus arteriosus stenting. We conducted a single centre retrospective chart review of neonates with ductal-dependent pulmonary blood flow who underwent patent ductus arteriosus stenting between January 1, 2014 and June 31, 2020. We compared patients variables between patients who underwent pre-procedural computed tomography imaging to those who did not. A total of 64 patients were referred for patent ductus arteriosus stenting with 33 (52%) obtaining pre-procedural computed tomography imaging. Average age [19 days; range 1–242 days (p = 0.85)] and weight [3.3 kg (range 2.2–6.0 kg; p = 0.19)] was not significantly different between the groups. A diagnosis of pulmonary atresia was made in 42 out of 64 (66%) patients prior to patent ductus arteriosus stenting. The cohort with pre-intervention computed tomography imaging had a significant reduction in the total number of access sites (1.2 versus 1.5; p = 0.03), contrast needed (5.9 versus 8.2 ml/kg; p = 0.008), fluoroscopy (20.7 versus 38.8 minutes; p = 0.02) and procedural time (83.4–128.4 minutes; p = 0.002) for the intervention. There was no significant difference in radiation burden between the groups (p = 0.35). Pre-procedural computed tomography imaging adds value by aiding interventional planning for neonatal patent ductus arteriosus stenting. A statistically significant reduction in the number of access sites, contrast exposure, as well as fluoroscopic and procedural time was noted without significantly increasing the cumulative radiation burden.

Development of the First Aliphatic 18F-Labeled Tetrazine Suitable for Pretargeted PET Imaging – Expanding the Bioorthogonal Tool Box

<p>Pretargeting imaging of nanomedicines have attracted considerable interest in nuclear medicine since it has the potential to increase imaging contrast while simultaneously reducing radiation burden to healthy tissue. Currently, the tetrazine ligation is the fastest bioorthogonal reaction available for this strategy and consequently, the state-of-art choice for <i>in vivo</i>chemistry. We have recently identified key properties for tetrazines to be applied in pretargeting. We have also developed a method to ¹⁸F-label highly reactive tetrazines using an aliphatic nucleophilic substitution strategy.<a> In this study, we combined this knowledge and developed an ¹⁸F-labeled tetrazine for pretargeted imaging. In order to develop this ligand, a small structure-property study was carried out. The most promising compound - with respect to reactivity, hydrophilicity and <i>ex vivo</i> blocking effect - was selected for labeling and subsequent PET <i>in vivo</i> imaging. Radiolabeling was achieved in satisfying radiochemical yields, molar activities as well as in high radiochemical purities. The tracer </a><a>displayed favorable pharmacokinetics and remarkable target-to-background ratios in pretargeted experiments - already one hour post injection.</a> We believe that the developed pretargeting imaging agent is a promising candidate for translation into clinical studies.</p>

Development of the First Aliphatic 18F-Labeled Tetrazine Suitable for Pretargeted PET Imaging – Expanding the Bioorthogonal Tool Box

<p>Pretargeting imaging of nanomedicines have attracted considerable interest in nuclear medicine since it has the potential to increase imaging contrast while simultaneously reducing radiation burden to healthy tissue. Currently, the tetrazine ligation is the fastest bioorthogonal reaction available for this strategy and consequently, the state-of-art choice for <i>in vivo</i>chemistry. We have recently identified key properties for tetrazines to be applied in pretargeting. We have also developed a method to ¹⁸F-label highly reactive tetrazines using an aliphatic nucleophilic substitution strategy.<a> In this study, we combined this knowledge and developed an ¹⁸F-labeled tetrazine for pretargeted imaging. In order to develop this ligand, a small structure-property study was carried out. The most promising compound - with respect to reactivity, hydrophilicity and <i>ex vivo</i> blocking effect - was selected for labeling and subsequent PET <i>in vivo</i> imaging. Radiolabeling was achieved in satisfying radiochemical yields, molar activities as well as in high radiochemical purities. The tracer </a><a>displayed favorable pharmacokinetics and remarkable target-to-background ratios in pretargeted experiments - already one hour post injection.</a> We believe that the developed pretargeting imaging agent is a promising candidate for translation into clinical studies.</p>

Predictability of Elimination and Excretion of Small Molecules from Animals to Humans, and Impact on Dosimetry for human ADME Studies with Radiolabeled Drugs

Background: We assessed the extent to which urinary and fecal excretion of 14C-labeled drug material in animal ADME studies was predictive of human ADME studies. We compared observed plasma elimination half lives for total drug related radioactivity in humans to pre-study predictions, and we estimated the impact of any major differences on human dosimetry calculations. Methods: We included 34 human ADME studies with doses of 14C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans versus animals; observed half life in humans versus predicted pre-study) and output parameters (effective dose post-study versus pre study) and assessed their relationship. Results: A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of 14C excreted in feces and the ratios of dosimetry outcomes in the entire dataset, but a statistically significant correlation was found when assessing the studies that were based on ICRP 60/62 (n=19 studies; P=0.0028). There also appeared to be a correlation between the plasma half-life ratios and the ratios of dosimetry results. A quantitative correlation assessment showed that there was a statistically significant correlation between these ratios (P<0.0001). Conclusion: In all cases where the plasma elimination half-life for 14C in humans was found to be longer than the predicted value, the radiation burden was still within ICRP Category IIa. Containment of the actual radiation burden below the limit of 1.00 mSv appeared to be determined partly also by our choice to limit 14C doses to 3.7 MBq.

Pretargeted Theranostics

Personalized medicine is becoming an integral part of our healthcare system, in which theranostics play a fundamental role. Nanomedicines such as monoclonal antibodies are a commonly used targeting vector in such approaches due to their outstanding targeting abilities as well as their capabilities to function as drug delivery vehicles. However, the application of nanomedicines in a clinical setting is connected with several challenges. For example, nanomedicines typically possess slow pharmacokinetics in respect to target accumulation and excretion. For targeted radionuclide therapy, this results in high radiation burden to healthy tissue. For drug delivery systems, long circulation and excretion times of the nanomedicine complicate site-specific release approaches and limit as such the usability of these strategies. One way to circumvent these challenges is the use of pretargeting strategies, which allow to separate the accumulation and excretion of nanomedicines from the actual diagnostic or therapeutic application. As such, pretargeting allows to use theranostic concepts utilizing the same nanomedicine and determine the success chances with diagnostic measures before initiating therapy. This chapter will explain the concept of pretargeted theranostics, which pretargeting systems have thus far been developed and compare how these systems performed.