213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer

Prostate-specific membrane antigen radioligand therapy (PSMA-RLT) with 177Lu-PSMA holds great promise as a safe treatment option in patients with metastasized castration-resistant prostate cancer (mCRPC) with appropriate selection. This approach, together with 68Ga-PSMA PET/CT, is an excellent example of theranostic nuclear medicine. However, more structured data have recently shown that despite a marked response to PSMARLT, some patients are refractory to 177Lu-radioligand therapy. Fortunately recent studies have demonstrated that targeted α-radiation therapy with 225Ac-PSMA can significantly benefit mCRPC patients. Similarly, 213Bi-DOTATOC may be able to break the radioresistance to β-emitters while simultaneously reducing haematological toxicity in patients with diffuse red marrow infiltration by neuroendocrine tumour.https://link.springer.com/journal/259am2018Nuclear Medicin

Novel radiolabeled bisphosphonates for PET diagnosis and endoradiotherapy of bone metastases

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the -emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec -1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Gaand 177Lu-labeled bisphosphonates offering improved pharmacological properties.The Deutsche Forschungsgemeinschaft (grant BE-2607/1-1/1-2 (Ralf Bergmann).http://www.mdpi.com/journal/pharmaceuticalsNuclear Medicin

A prospective intra-individual comparison of [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGAZOL PET/CT, and [99mTc]Tc-MDP bone scintigraphy for radionuclide imaging of prostate cancer skeletal metastases

Please read abstract in the article.http://link.springer.com/journal/259hj2022Nuclear Medicin

VUV frequency combs from below-threshold harmonics

Recent demonstrations of high-harmonic generation (HHG) at very high repetition frequencies (~100 MHz) may allow for the revolutionary transfer of frequency combs to the vacuum ultraviolet (VUV). This advance necessitates unifying optical frequency comb technology with strong-field atomic physics. While strong-field studies of HHG have often focused on above-threshold harmonic generation (photon energy above the ionization potential), for VUV frequency combs an understanding of below-threshold harmonic orders and their generation process is crucial. Here we present a new and quantitative study of the harmonics 7-13 generated below and near the ionization threshold in xenon gas. We show multiple generation pathways for these harmonics that are manifested as on-axis interference in the harmonic yield. This discovery provides a new understanding of the strong-field, below-threshold dynamics under the influence of an atomic potential and allows us to quantitatively assess the achievable coherence of a VUV frequency comb generated through below threshold harmonics. We find that under reasonable experimental conditions temporal coherence is maintained. As evidence we present the first explicit VUV frequency comb structure beyond the 3rd harmonic.Comment: 16 pages, 4 figures, 1 tabl

Macrocyclic bisphosphonates for PET-diagnosis and endoradiotherapy of bone metastases

Die Fallzahlen von Prostata- und Brustkrebs nehmen aktuell die Spitzenplätze bei Krebserkrankungen weltweit ein. Eine schwerwiegende Folge dieser Erkrankung stellen Metastasierungen in das Knochengewebe dar, welche zu einer dramatischen Verschlechterung des Allgemeinzustandes und der Lebensqualität des Patienten führen. Die Symptome sind gekennzeichnet durch enorme Schmerzen in Kombination mit osteoblastischen und osteolytischen Knochenveränderungen, bis hin zu Frakturen und spinalen Kompressionssyndromen, sowie einer metabolischen Hypercalcaemie.rnBei der Diagnose und Therapie nehmen verschiedene Radiopharmaka eine Schlüsselrolle ein. Konjugate aus makrozyklischen Chelatoren und knochenaffinen Bisphosphonaten stellen ein geeignetes Mittel dar als so genannte Theranostika, die Diagnose und Therapie in einem Molekül vereinen. Hierbei konnten mit dem Generator basierenden PET-Nuklid 68Ga(III) und dem Therapienuklid 177Lu(III) erste Erfolge mit der Verbindung BPAMD am Patienten erzielt werden. Im Rahmen der vorliegenden Arbeit ist es gelungen, die pharmakologischen Eigenschaften der BPAMD-Leitstruktur weiter zu optimieren und neue Derivate erfolgreich zu synthetisieren. Diese zeichneten sich durch eine erhöhte Knochenaffinität und eines besseren ´target to background´ Verhältnisses aus. Im Zuge der Derivatisierung ist es außerdem gelungen, erfolgreich eine Substanz darzustellen, welche über eine gesteigerte Blutretention verfügt und die letztendlich die Bioverfügbarkeit des Tracers erhöhte. Verbindungen solchen Typs können zu einem besseren Tumor zu gesundem Knochen Verhältnis beitragen und eventuell einen höheren Therapieerfolg erzielen. Eines dieser neuen vielversprechenden Bisphosphonate, [68Ga]NO2APBP konnte innerhalb einer klinischen Phase 0 bzw. I sein großes Potential als Diagnostikum zur Erfassung von Skelettmetastasen unter Beweis stellen. Innerhalb einer Testreihe mit 12 Patienten wurde eine hohe diagnostische Übereinstimmung mit dem Goldstandard 18F-Fluorid erreicht. In ausgesuchten Metastasen konnte sogar eine höhere Tracer-Aufnahme erzielt werden.rnIn Zukunft können makrozyklische Bisphosphonate eine wichtige Rolle bei der palliativen Schmerztherapie von Knochenmetastasen einnehmen. rnProstate and breast cancer are high rated in the numbers of cancer cases worldwide. The serious consequence of this disease is the metastatic spread of the cancer into the bones. It is associated with severe bone pain, spinal cord compression, skeletal fractures and a metabolic hypercalceamie. Finally, the symptoms reduce the patients quality of life dramatically.rnRadiopharmaceuticals play a key role in the assessment and therapy of this disease. Conjugates of macrocyclic chelates and bone affine bisphosphonates are an appropriate means, as so called theranostics, to unite diagnosis and therapy in one molecule. In this connection the generator based PET-nuclide 68Ga(III) and the therapy nuclide 177Lu(III) showed promising first results with BPAMD in initial patient studies. For both trivalent radiometals, new derivatives were successful synthesized deduced by further developments of the BPAMD lead structure with enhanced pharmacological properties. These novel compounds, based on the modern osteoporosis drugs pamidronate and zoledronate, distinguished by an increased bone affinity and a superior target to background ratio. In addition it was also succeeded to develop a derivative of longer blood retention, which finally resulted in an enhanced bioavailability of the tracer. This class of bisphosphonate enables an increased tumor to healthy bone ratio, which might end up in an improved therapeutic success. One of these novel macrocyclic bisphosphonates, [68Ga]NO2APBP showed superior results in the animal testing and was therefore chosen for an initial clinical phase 0 and I trials. Within this study the compound was able to underline its high diagnostic efficiency in combination with 68Ga-PET. The first series of tests in 12 patients revealed a similar compliance in the detection capability of skeletal metastases as the gold standard 18F-fluoride. Moreover in selected metastatic foci a higher uptake of the bisphosphonate could be obtained. rnThe promising results indicate that in future the macrocyclic bisphosphonate concept may play a key role in the management of skeletal metastases in nuclear mediciner

Gallium(iii) complexes of nota-bis (phosphonate) conjugates as pet radiotracers for bone imaging

Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP)) or methylenephosphinate (NO2AP(BP)) spacers designed for Ga-68 were prepared. Ga-III complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added Ga-68. For both ligands, formation of Ga-III complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 degrees C and in a narrow acidity region (pH similar to 3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the Ga-68 complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 +/- 1.27 for [Ga-68]NO2AP(BP)) at 60min p.i., which is superior to uptake of Ga-68-DOTA-based bis(phosphonates) and [F-18]NaF reported earlier (SUV of 4.63 +/- 0.38 and SUV of 4.87 +/- 0.32 for [Ga-68]DO3AP(BP) and [F-18]NaF, respectively, at 60min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 +/- 0.09 for [Ga-68]NO2AP(BP) at 60min p.i.), revealing the new Ga-68 complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT

Development of a [lu-177]bpamd labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy

Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [Lu-177]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy beta(-) emitting therapeutic radiolanthanide Lu-177. For routine chemical application, an automated synthesis of this radiopharmaceutical and a Kit-type labeling procedure appears to be a basic requirement for its good manufacturing practice (GMP) based production. A Kit formulation combining BPAMD, acetate buffer, and ethanol resulted in almost quantitative labeling yields. The use of ethanol and ascorbic acid as quenchers prevented radiolysis over 48 hours. An automated synthesis unit was designed for the production of therapeutic doses of [Lu-177]BPAMD up to 5 GBq. The procedure was successfully applied for patient treatments

Synthesis and Preliminary <i>in Vivo</i> Evaluation of Well-Dispersed Biomimetic Nanocrystalline Apatites Labeled with Positron Emission Tomographic Imaging Agents

In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their <i>in vivo</i> behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs (“naked” and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([¹⁸F]­NaF and ⁶⁸Ga-NO2AP^BP) was investigated. [¹⁸F]­NaF was used for the direct incorporation of the radioisotope into the crystal lattice, while the labeling by surface functionalization was accomplished by using ⁶⁸Ga-NO2AP^BP (a new radio-metal chelating agent). The labeling results with both tracers were fast, straightforward, and reproducible. AP-NPs demonstrated excellent ability to bind relevant quantities of both radiotracers and good <i>in vitro</i> stability in clinically relevant media after the labeling. <i>In vivo</i> PET studies in healthy Wistar rats established that the radiolabeled AP-NPs gave significant PET signals and they were stable over the investigated time (90 min) since any tracer desorption was detected. These preliminary <i>in vivo</i> studies furthermore showed a clear ability of citrated versus naked AP-NPs to accumulate in different organs. Interestingly, contrary to naked AP-NPs, citrated ones, which unveiled higher colloidal stability in aqueous suspensions, were able to escape the first physiological filter, i.e., the lungs, being then accumulated in the liver and, to a lesser extent, in the spleen. The results of this work, along with the fact that AP-NPs can be also functionalized with targeting ligands, with therapeutic agents, and also with metals for a combination of different imaging modalities, make AP-NPs very encouraging materials for further investigations as theranostic agents in nanomedicine

Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC

Introduction PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. Methods Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. Results [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. Conclusion Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.ISSN:1619-7070ISSN:1619-708