Publikationen

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis group (IOTA) and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based consensus statements on the pre-operative diagnosis of ovarian tumours, including imaging techniques, biomarkers and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group consisting of expert practising clinicians and researchers who have demonstrated leadership and expertise in the pre-operative diagnosis of ovarian tumours and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence based, the current literature was reviewed and critically appraised. Preliminary consensus statements were drafted based on a review of the relevant literature. During a conference call, the whole group discussed each preliminary consensus statement and a first round of voting was organised. Statements were removed when a consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. Then the consensus statements were revised accordingly. Another round of voting was organised according to the same rules to allow the whole group to evaluate the revised version of the consensus statements. The group achieved consensus on 18 statements. This article presents these ESGO/ISUOG/IOTA/ESGE consensus statements on the pre-operative diagnosis of ovarian tumours and to the assessment of carcinomatosis, together with a summary of evidence supporting each statement. This article is protected by copyright. All rights reserved.

Hyperparathyroidism-jaw-tumor syndrome (HPT-JTS) is a rare autosomal dominant disorder. A typical manifestation of HPT-JTS is the association of jaw-ossifying fibroma with primary hyperparathyroidism. Due to its rarity and diversity in its manifestations, it is a challenging diagnosis. A 33-year-old female patient was referred due to painful swelling of the right maxilla suggestive of malignancy. The clinical presentations were not conclusive until she underwent F18-fluorodeoxyglucose positron emission tomography/computed tomography (F18-FDG PET/CT). F18-FDG PET/CT proved to be a useful tool to assist the clinicians in visualizing the "bigger picture" and, therefore all manifestation as pieces of "one puzzle."

Nuclear medicine parathyroid imaging is important in the identification of hyperfunctioning parathyroid glands in primary hyperparathyroidism (pHPT), but it may be also valuable before surgical treatment in secondary hyperparathyroidism (sHPT). Parathyroid radionuclide imaging with scintigraphy or positron emission tomography (PET) is a highly sensitive procedure for the assessment of the presence and number of hyperfunctioning parathyroid glands, located either at typical sites or ectopically. The treatment of pHPT is mostly directed toward minimally invasive parathyroidectomy, especially in cases with a single adenoma. In experienced hands, successful surgery depends mainly on the exact preoperative localization of one or more hyperfunctioning parathyroid adenomas. Failure to preoperatively identify the hyperfunctioning parathyroid gland challenges minimally invasive parathyroidectomy and might require bilateral open neck exploration.

To investigate the possibility of reducing the injected activity for whole-body [18F]FDG-PET/CT studies of paediatric oncology patients and to assess the usefulness of time-of-flight (TOF) acquisition on PET image quality at reduced count levels.

The recommendations cover indications for MRI examination including acquisition planes, patient preparation, imaging protocol including multi-parametric approaches such as diffusion-weighted imaging (DWI-MR),  dynamic contrast-enhanced imaging (DCE-MR) and standardised reporting. The document also underscores the value of whole-body 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) and highlights potential future methods.

The development of highly selective and fast biocompatible reactions for ligation and cleavage has paved the way for new diagnostic and therapeutic applications of pretargeted chemistry. The concept of bioorthogonal pretargeting has attracted considerable interest, in particular for the targeted delivery of radionuclides and drugs. In nuclear medicine, pretargeting can provide increased target-to-background ratios at early time-points compared to traditional approaches. This reduces the radiation burden to healthy tissue and, depending on the selected radionuclide, enables better imaging contrast or higher therapeutic efficiency. Moreover, bioorthogonally triggered cleavage of pretargeted antibody-drug conjugates represents an emerging strategy to achieve controlled release and locally increased drug concentrations. The toolbox of bioorthogonal reactions has significantly expanded in the past decade, with the tetrazine ligation being the fastest and one of the most versatile chemistries. Progress in the field, however, relies heavily on the development and evaluation of (radio)labeled compounds, preventing the use of compound libraries for systematic studies. The rational design of tetrazine probes and triggers has thus been impeded by the limited understanding of the impact of structural parameters on the ligation performance. In this work, we describe the development of a pretargeted blocking assay that allows for the investigation of the fate of a structurally diverse library of 45 unlabeled tetrazines and their capability to reach and react with pretargeted -cyclooctene (TCO)-modified antibodies in tumor-bearing mice. This study enabled us to assess the correlation of click reactivity and lipophilicity of tetrazines with their performance. In particular, high rate constants (>50 000 M s) for the reaction with TCO and low calculated log values (below -3) of the tetrazine were identified as strong indicators for successful pretargeting. Radiolabeling gave access to a set of selected F-labeled tetrazines, including highly reactive scaffolds, which were used in pretargeted PET imaging studies to confirm the results from the blocking study. These insights thus enable the rational design of tetrazine probes for application and will thereby assist the clinical translation of bioorthogonal pretargeting.

Ga-DOTATOC represents a useful tool in tumor contouring for radiosurgery planning. We present a case series of patients affected by meningiomas on who we performed Ga-DOTATOC positron emission tomography (PET)/CT pre-operatively, a subgroup of which also underwent a post-operative Ga-DOTATOC PET/CT to evaluate the standardized uptake value (SUV) modification after Gamma Knife ICON treatment in single or hypofractionated fractions. Twenty patients were enrolled/included in this study: ten females and ten males. The median age was 52 years (range 33-80). The median tumor diameter was 3.68 cm (range 0.12-22.26 cm), and the median pre-radiotherapy maximum SUV value was 11 (range 2.3-92). The average of the relative percentage changes between SUVs at baseline and follow up was -6%, ranging from -41% to 56%. The SUV was reduced in seven out of 12 patients (58%), stable in two out of 12 (17%), and increased in three out of 12 (25%), suggesting a biological response of the tumor to the Gamma Knife treatment in most of the cases. Ga-DOTATOC-PET represents a valuable tool in assessing the meningioma diagnosis for primary radiosurgery; it is also promising for follow-up assessment.

Peptide receptor radionuclide therapy (PRRT) has been recognized as a promising therapy against neuroendocrine tumors (NETs). The use of F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) in NETs has been a matter of controversy. The purpose of this study was to evaluate the long-term survival and efficacy of a second PRRT course with Lu-DOTATE in patients with advanced gastroenteropancreatic (GEP) NETs. Furthermore, the value of F-FDG PET/CT in these patients was evaluated. 40 patients with GEP NETs who underwent two PRRT courses with Lu-DOTATATE and combined examinations with Ga-DOTA-TOC and F-FDG PET/CT were evaluated. After the second PRRT course, two patients (5.0%) were in partial remission, 21 patients (52.5%) in stable disease and 17 patients (42.5%) had progressive disease. The median overall survival was 122.10 months. After the second PRRT course, the median overall survival was significantly higher ( = 0.033) in the F-FDG-negative group compared to the F-FDG-positive group (145.50 versus 95.06 months, respectively). The median time to progression was 19.37 months. In conclusion, a second PRRT course with Lu-DOTATE is an effective treatment approach for GEP NET patients with disease progression. A change in F-FDG status after PRRT may predict the disease course and survival. Patients who are F-FDG-negative have a significantly longer overall survival than those who are F-FDG-positive.

: This study investigated the performance of ensemble learning holomic models for the detection of breast cancer, receptor status, proliferation rate, and molecular subtypes from [F]FDG-PET/CT images with and without incorporating data pre-processing algorithms. Additionally, machine learning (ML) models were compared with conventional data analysis using standard uptake value lesion classification. : A cohort of 170 patients with 173 breast cancer tumors (132 malignant, 38 benign) was examined with [F]FDG-PET/CT. Breast tumors were segmented and radiomic features were extracted following the imaging biomarker standardization initiative (IBSI) guidelines combined with optimized feature extraction. Ensemble learning including five supervised ML algorithms was utilized in a 100-fold Monte Carlo (MC) cross-validation scheme. Data pre-processing methods were incorporated prior to machine learning, including outlier and borderline noisy sample detection, feature selection, and class imbalance correction. Feature importance in each model was assessed by calculating feature occurrence by the R-squared method across MC folds. : Cross validation demonstrated high performance of the cancer detection model (80% sensitivity, 78% specificity, 80% accuracy, 0.81 area under the curve (AUC)), and of the triple negative tumor identification model (85% sensitivity, 78% specificity, 82% accuracy, 0.82 AUC). The individual receptor status and luminal A/B subtype models yielded low performance (0.46-0.68 AUC). SUV model yielded 0.76 AUC in cancer detection and 0.70 AUC in predicting triple negative subtype. : Predictive models based on [F]FDG-PET/CT images in combination with advanced data pre-processing steps aid in breast cancer diagnosis and in ML-based prediction of the aggressive triple negative breast cancer subtype.

Traumatic brain injuries can lead to long-term mental seizures that are difficult to differentiate from dissociative psychogenic symptoms, respectively, psychogenic nonepileptic seizures. Recent articles have drawn attention to the need of differentiation of psychological and brain trauma-related symptoms in survivors of violence. This case study reflects a diagnostic step in a 20-year-male who reported to have been subjected to torture, including blunt force to the head 2 years before examination. He suffers from episodical headaches followed by mental bouts of aggression and restlessness. We performed a brain F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography to identify a cerebral correlate of the psychogenic seizures. The examination yielded a hypermetabolic focus in the frontal superior parasagittal region. Psychogenic seizures can frequently be observed as culture-specific "idioms of distress" and can challenge diagnostic evaluation, especially in the victims of violence with an additional history of blunt brain trauma. The advances in molecular imaging such as PET can be expected to play a crucial role in forensic and clinical assessment in the increasing number of such patients.

Nuclear medicine parathyroid imaging is important in the identification of hyperfunctioning parathyroid glands in primary hyperparathyroidism (pHPT), but it may be also valuable before surgical treatment in secondary hyperparathyroidism (sHPT). Parathyroid radionuclide imaging with scintigraphy or positron emission tomography (PET) is a highly sensitive procedure for the assessment of the presence and number of hyperfunctioning parathyroid glands, located either at typical sites or ectopically. The treatment of pHPT is mostly directed toward minimally invasive parathyroidectomy, especially in cases with a single adenoma. In experienced hands, successful surgery depends mainly on the exact preoperative localization of one or more hyperfunctioning parathyroid adenomas. Failure to preoperatively identify the hyperfunctioning parathyroid gland challenges minimally invasive parathyroidectomy and might require bilateral open neck exploration.

This study sought to describe worldwide variations in the use of myocardial perfusion imaging hardware, software, and imaging protocols and their impact on radiation effective dose (ED).

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project "TECANT" two Tc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log , protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [Tc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [Tc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [Tc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [Tc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [Tc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [Tc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [Tc]Tc-TECANT-1 for clinical translation of the first Tc-based SST2 antagonist.

We sought to evaluate the behavior of cardiac mechanical synchrony as measured by phase SD (PSD) derived from gated MPI SPECT (gSPECT) in patients with super-response after CRT and to evaluate the clinical and imaging characteristics associated with super-response.

To analyze the evolution post-cardiac resynchronization therapy (CRT) in left ventricular non-compaction (LVNC) cardiomyopathy (CM) patients compared to other types of CM, according to clinical and functional variables, by using gated-SPECT myocardial perfusion imaging (MPI).

Gated myocardial perfusion scintigraphy (GMPS) phase analysis is an important tool to investigate the physiology of left ventricular (LV) dyssynchrony. We aimed to test the performance of GMPS LV function and phase analysis in different clinical settings and on a diverse population.

Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring.

The prognostic value of left ventricular (LV) mechanical dyssynchrony (MD) in patients with LV aneurysm (LVA) is unclear. This study aimed to investigate the long-term prognostic value of LVMD in LVA patients.

In positron emission tomography (PET) imaging, accurate clinical assessment is often affected by the partial volume effect (PVE) leading to overestimation (spill-in) or underestimation (spill-out) of activity in various small regions. The spill-in correction, in particular, can be very challenging when the target region is close to a hot background region. Therefore, this study evaluates and compares the performance of various recently developed spill-in correction techniques, namely: background correction (BC), local projection (LP), and hybrid kernelized (HKEM) methods. We used a simulated digital phantom and [F]-NaF PET data of three patients with abdominal aortic aneurysms (AAA) acquired with Siemens Biograph mMR™ and mCT™ scanners respectively. Region of Interest (ROI) analysis was performed and the extracted , and target-to-background ratio (TBR) scores were compared. Results showed substantial spill-in effects from hot regions to targeted regions, which are more prominent in small structures. The phantom experiment demonstrated the feasibility of spill-in correction with all methods. For the patient data, large differences in , and scores were observed between the ROIs drawn over the entire aneurysm and ROIs excluding some regions close to the bone. Overall, BC yielded the best performance in spill-in correction in both phantom and patient studies.

The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing gallium-labelled somatostatin analogue ([Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing fluorine-fluoro-2-deoxyglucose ([F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [F]FDG and [Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.

Targeted radionuclide therapies (TRT) using I-metaiodobenzylguanidine (I-MIBG) and peptide receptor radionuclide therapy (Lu or Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-I-MIBG therapy was approved by the FDA and both Lu-DOTATATE and I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Peptide receptor radionuclide therapy (PRRT) has been recognized as a promising therapy against neuroendocrine tumors (NETs). The use of F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) in NETs has been a matter of controversy. The purpose of this study was to evaluate the long-term survival and efficacy of a second PRRT course with Lu-DOTATE in patients with advanced gastroenteropancreatic (GEP) NETs. Furthermore, the value of F-FDG PET/CT in these patients was evaluated. 40 patients with GEP NETs who underwent two PRRT courses with Lu-DOTATATE and combined examinations with Ga-DOTA-TOC and F-FDG PET/CT were evaluated. After the second PRRT course, two patients (5.0%) were in partial remission, 21 patients (52.5%) in stable disease and 17 patients (42.5%) had progressive disease. The median overall survival was 122.10 months. After the second PRRT course, the median overall survival was significantly higher ( = 0.033) in the F-FDG-negative group compared to the F-FDG-positive group (145.50 versus 95.06 months, respectively). The median time to progression was 19.37 months. In conclusion, a second PRRT course with Lu-DOTATE is an effective treatment approach for GEP NET patients with disease progression. A change in F-FDG status after PRRT may predict the disease course and survival. Patients who are F-FDG-negative have a significantly longer overall survival than those who are F-FDG-positive.

Dose response of 22 patients experiencing mCRPC (metastatic castration-resistant prostate cancer) to Lu-PSMA I&T radionuclide therapy was investigated. Dosimetry calculations are used to assess correlations between dosimetric quantities and biomarker values.

The successful use of theranostic twins in neuroendocrine tumors (NET) was the pioneering approach to radionuclide therapy in other tumor types. 64Cu/18F PSMA for molecular imaging with PET-CT and peptide radioligand therapy (PRLT) with 177Lu labeled PSMA inhibitors are the next theranostic twins in nuclear medicine. 68Ga/ 64Cu/18F PSMA PET-CT detects metastatic prostate cancer with high diagnostic sensitivity and specificity and can be used to select patients for PRLT and evaluate therapy response. Radionuclide therapy with 177Lu-PSMA inhibitors has been shown to be effective in the treatment of metastatic CRPC.

Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance the quality of life. Radiopharmaceuticals are mainly used in the latest courses of the disease. Bone-pain palliation with easy-to-administer radionuclides offers advantages, including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other therapies. Several β¯- and α-emitters as well as pharmaceuticals, from the very first [Sr]strontium-dichloride to recently introduced [Ra]radium-dichloride, are investigated to identify an optimum agent. In addition, the combination of bone-seeking radiopharmaceuticals with chemotherapy or radiotherapy has been employed to enhance the outcome. Radiopharmaceuticals demonstrate an acceptable response rate in pain relief. Nevertheless, survival benefits have been documented in only a limited number of studies. In this review, we provide an overview of bone-seeking radiopharmaceuticals used for bone-pain palliation, their effectiveness and toxicity, as well as the results of the combination with other therapies. Bone-pain palliation with radiopharmaceuticals has been employed for eight decades. However, there are still new aspects yet to be established.

Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms characterised by variable endocrine activity and somatostatin receptor expression, with the latter allowing the use of targeted therapeutic concepts. Currently accepted treatment strategies for advanced well-differentiated NET include somatostatin analogues octreotide and lanreotide, peptide receptor radionuclide therapy using radiolabelled somatostatin analogues, mammalian target of Rapamycin inhibitor everolimus, tyrosine kinase inhibitor sunitinib, interferon alpha and classical cytostatic, such as streptozotocin-based and temozolomide-based treatment. Indication, use and approval of these treatments differ based on primary tumour origin, grading and symptomatic burden and require an optimised multidisciplinary cooperation of medical oncologists, endocrinologists and nuclear medicine specialists. Interestingly, hot topics in oncology including immunotherapy and use of next-generation-sequencing techniques currently play a minor role for the treatment of NETs. The recent revision of the WHO classification including the recognition of the novel NET G3 category allows for potentially more tailored treatment strategies in the near future. However, this new entity also poses a therapeutic challenge as only limited data are currently available. The present article aims to provide an overview on our personal treatment concepts for advanced NETs with a focus on tumours of gastroenteropancreatic origin.

Peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-DOTA,TYR-octreotate ([Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [Lu]Lu-DOTA-TATE in female Lewis rats.

Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide--polypeptoid polymers (PeptoBrushes) functionalized with -cyclooctene (TCO). The complementary In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.

To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC).