Radiopharmaceutical formulation and preliminary clinical dosimetry of [Lu]Lu-DOTA-MGS5 for application in peptide receptor radionuclide therapy.

Purpose: Radiolabelled minigastrin (MG) analogues targeting the cholecystokinin-2 receptor (CCK2R) have proven to be a promising approach for peptide receptor radionuclide therapy (PRRT). In this study, we report on the radiopharmaceutical development and standardization of the preparation of [Lu]Lu-DOTA-MGS5 using an automated synthesis module. Furthermore, we present the preclinical tests required to move forward towards a first therapeutic clinical trial as well as preliminary clinical dosimetry data.

Single-time-point dosimetry using model selection and the Bayesian fitting method: A proof of concept.

Purpose: This study aimed to determine the effect of model selection on simplified dosimetry for the kidneys using Bayesian fitting (BF) and single-time-point (STP) imaging.

Methods: Kidney biokinetics data of [Lu]Lu-PSMA-617 from mHSPC were collected using SPECT/CT after injection of (3.1 ± 0.

EANM expert opinion: How can lessons from radiobiology be applied to the design of clinical trials? Part I: back to the basics of absorbed dose-response and threshold absorbed doses.

Purpose: This study by the EANM radiobiology working group aims to analyze the efficacy and toxicity of targeted radionuclide therapy (TRT) using radiopharmaceuticals approved by the EMA and FDA for neuroendocrine tumors and prostate cancer. It seeks to understand the correlation between physical parameters such as absorbed dose and TRT outcomes, alongside other biological factors.

Methods: We reviewed clinical studies on TRT, focusing on the relationship between physical parameters and treatment outcomes, and applying basic radiobiological principles to radiopharmaceutical therapy to identify key factors affecting therapeutic success.

Accuracy of holmium-166 SPECT/CT quantification over a large range of activities.

Background: Quantitative imaging is a crucial step for dosimetry in radionuclide therapies. Traditionally, SPECT/CT imaging is quantified based on scanner-specific conversion factors or self-calibration, but recently absolute quantification methods have been introduced in commercial SPECT reconstruction software (Broad Quantification, Siemens Healthineers). In this phantom study we investigate the accuracy of three quantification methods for holmium-166 SPECT/CT imaging, and provide recommendations for clinical dosimetry.

Treatment of [99mTc]Tc-hydroxy-diphosphonate ([99mTc]Tc-HDP) extravasation using hyaluronidase.

Extravasation of 99mTc-labeled radiopharmaceuticals is generally considered to require no specific intervention. In the presented case, the use of hyaluronidase could have minimized the adverse effects resulting from such an extravasation. Currently, no guidelines exist regarding the use of hyaluronidase after extravasation of [99mTc]Tc-HDP.

Evaluation of a novel Lu-labelled therapeutic Affibody molecule with a deimmunized ABD domain and improved biodistribution profile.

Purpose: Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required.

Methods: The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine.

Towards effective CAIX-targeted radionuclide and checkpoint inhibition combination therapy for advanced clear cell renal cell carcinoma.

Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity.

Bone marrow dosimetry in low volume mHSPC patients receiving Lu-177-PSMA therapy using SPECT/CT.

Background: Bone marrow toxicity in advanced prostate cancer patients who receive [Lu]Lu-PSMA-617 is a well-known concern. In early stage patients; e.g.

Implementing Ac-225 labelled radiopharmaceuticals: practical considerations and (pre-)clinical perspectives.

Background: In the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide.

Main Body: Ac-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis.

Evaluation of the tolerability and safety of [Ac]Ac-PSMA-I&T in patients with metastatic prostate cancer: a phase I dose escalation study.

Background: Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10-20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC.

Replacing Lu-177 with Tb-161 in DOTA-TATE and PSMA-617 therapy: potential dosimetric implications for activity selection.

Aim: To explore the dosimetric effect of substituting Lu-177 with Tb-161 in targeted radionuclide therapy (TRT) using the registered tracers DOTA-TATE and PSMA-617.

Methods: Using established kinetic data for [Lu]Lu-DOTA-TATE and [Lu]Lu-PSMA-617, radiation absorbed doses to typical tumour lesion as well as non-target tissues ([Lu]Lu-DOTA-TATE: kidneys, spleen and liver, [Lu]Lu-PSMA-617: kidneys, liver and salivary glands) were calculated for Lu-177 and Tb-161.

Results: For both DOTA-TATE and PSMA-617, the substitution of Lu-177 with Tb-161 results in an increase in the delivered dose per unit of activity to tumour tissue by 40%.

The Balance Between the Therapeutic Efficacy and Safety of [Lu]Lu-NeoB in a Preclinical Prostate Cancer Model.

Purpose: Radiolabeled NeoB is a promising gastrin-releasing peptide receptor (GRPR)-targeting radiopharmaceutical for theranostics of GRPR-expressing malignancies, e.g., prostate cancer (PCa).

[Pb]Pb-eSOMA-01: A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (Pb) represents a promising avenue. A series of ligands based on octreotate was developed.

Urinary excretion kinetics of [Lu]Lu-PSMA-617.

Introduction: For the implementation of suitable radiation safety measures in [Lu]Lu-PSMA-617 therapy, additional insight into excretion kinetics is important. This study evaluates this kinetics in prostate cancer patients via direct urine measurements.

Methods: Both the short-term (up to 24 h, n = 28 cycles) and long-term kinetics (up to 7 weeks, n = 35 samples) were evaluated by collection of urine samples.

First preclinical evaluation of [Ac]Ac-DOTA-JR11 and comparison with [Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs.

Background: The [Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters.

New Radiolabeled Exendin Analogues Show Reduced Renal Retention.

PET imaging of the glucagon-like peptide-1 receptor (GLP-1R) using radiolabeled exendin is a promising imaging method to detect insulinomas. However, high renal accumulation of radiolabeled exendin could hamper the detection of small insulinomas in proximity to the kidneys and limit its use as a radiotherapeutic agent. Here, we report two new exendin analogues for GLP-1R imaging and therapy, designed to reduce renal retention by incorporating a cleavable methionine-isoleucine (Met-Ile) linker.

Joint EANM/SNMMI procedure guideline for the use of Lu-labeled PSMA-targeted radioligand-therapy (Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug.

Optimization of the radiation dosimetry protocol in Lutetium-177-PSMA therapy: toward clinical implementation.

Background: Dosimetry in [Lu]Lu-PSMA therapy is a valuable tool to assess treatment efficacy and toxicity. This study aims to develop a clinically implementable protocol to determine the absorbed dose in organs and tumor lesions after [Lu]Lu-PSMA-617 therapy, by reducing the imaging time points and utilizing population-based kinetics with a single scan, with evaluation of its influence on the uncertainty in absorbed dose.

Methods: Ten patients with metastatic hormone-sensitive prostate cancer received two cycles of [Lu]Lu-PSMA-617.

Kidney absorbed radiation doses for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T determined by 3D clinical dosimetry.

Purpose: For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T, using an identical dosimetry protocol.

Efficacy and safety of peptide receptor radionuclide therapy with [Lu]Lu-DOTA-TATE in 15 patients with progressive treatment-refractory meningioma.

Purpose: There is no evidence-based systemic therapy for patients with progressive meningiomas for whom surgery or external radiotherapy is no longer an option. In this study, the efficacy and safety of peptide receptor radionuclide therapy (PRRT) in patients with progressive, treatment-refractory meningiomas were evaluated.

Methods: Retrospective analysis of all meningioma patients treated with [Lu]Lu-DOTA-TATE from 2000 to 2020 in our centre.