^99mTc-PSMA Radioliganden für die SPECT Bildgebung von Prostatakrebs – Eine Alternative zu PET?

Zusammenfassung

Ziel Prostatakrebs ist die am häufigsten diagnostizierte Krebserkrankung bei Männern und gehört weltweit zu den häufigsten Todesursachen infolge Krebs. Eine präzise und sensitive Methode zur Diagnose der Krankheit, insbesondere bei Metastasierung ist von größter Bedeutung. Das Prostata-spezifische Membran-Antigen (PSMA), auch unter dem Namen Folathydrolase I oder Glutamat Carboxypeptidase II bekannt, ist in fast allen Fällen von Prostatakrebs inklusive deren Metastasen überexprimiert, was das Protein für das Tumor-Targeting außerordentlich interessant macht. Die Entwicklung des Liganden PSMA-11, radioaktiv markiert mit dem Positronenemitter ⁶⁸Ga, hat sich in wenigen Jahren als neuer „Goldstandard“ für die nuklearmedizinische Untersuchung des metastasierenden Prostatakarzinoms etabliert und die Cholin-basierten Radiotracer ¹¹C- und ¹⁸F-Cholin fast verdrängt. Trotz der erfolgreichen Anwendung von ⁶⁸Ga-PSMA-11 darf nicht vergessen werden, dass Gammakameras weitverbreiteter sind als PET-Scanner und Technetium-99 m (^99 mTc) immer noch das am häufigsten verwendete Radionuklid in der Nuklearmedizin repräsentiert. Dieser Übersichtsartikel fasst die relevanten Entwicklungen ^99 mTc-basierter PSMA-Radioliganden in den letzten Jahren zusammen.

Ergebnisse Verschiedene Arbeitsgruppen haben aus diesem Grund in den letzten Jahren gezielt Verbindungen entwickelt, die an PSMA binden und mit ^99 mTc markiert werden können. Eine Reihe von ^99 mTc-Radioliganden wurde bereits erfolgreich klinisch getestet. 3 grundlegende Parameter wurden variiert respektive untersucht: 1) Das Chelatorsystem bzw. die Oxidationsstufe des Metallzentrums; 2) die Linkereinheit zwischen dem ^99 mTc-Komplex und der PSMA-bindenden Einheit und 3) die PSMA-bindende Einheit. Für ^99 mTc in der Oxidationsstufe + V wurden vielfach tetradentate Derivate von MAG₃ (Mercaptoacetyltriglycin) aber auch Hydrazinonikotinsäure (HYNIC) erfolgreich eingesetzt. Der ^99 mTc-Tricarbonyl-Kern wird in Kombination mit tridentaten Chelatoren für die Koordination von ^99 mTc in der Oxidationsstufen + I verwendet. Ferner wurden Linkereinheiten verschiedener Länge und mit respektive ohne aromatische Seitenketten getestet. Dabei zeigten Derivate mit Chelatoren und Linkereinheiten mit einer höheren Hydrophilie meistens eine raschere Pharmakokinetik. Radioliganden mit aromatischen Seitenketten im Linker zeigten eine höhere Anreicherung und Retention im Tumorgewebe. Kleine Unterschiede wurden bei Derivaten mit den PSMA-bindenden Einheiten Glutamat-Urea-Glutamat und Glutamat-Urea-Lysin beobachtet. Die alternative PSMA-bindende Einheit (2[(3-Amino-3-Carboxypropyl)(Hydroxy)(Phosphinyl)-Methyl]Pentan-1,5-Disäure) (GPI) wurde auch zur Markierung mit ^99 mTc funktionalisiert, jedoch haben ^99 mTc-DPI Derivate bisher die klinische Phase nicht erreicht.

Schlussfolgerungen Basierend auf den momentanen klinischen Resultaten ist noch unklar, welcher der ^99 mTc-basierten Radioliganden sich für das PSMA-Targeting klinisch durchsetzen wird. Dazu braucht es ausgedehntere und insbesondere (mit ⁶⁸Ga-PSMA-11 als Goldstandard) vergleichende klinische Studien. Es steht allerding außer Frage, dass ^99 mTc-basierte PSMA-Radioliganden in die nuklearmedizinische Routine Einzug halten werden.

Abstract

Aim Prostate cancer is the most often diagnosed cancer type in men and belongs to the worldwide most frequent cause of cancer deaths. Precise and sensitive methods for diagnosis of the disease, in particular,when the disease has already metastasised, is of critical importance. The prostate-specific membrane antigen (PSMA), also known as folate hydrolase I or glutamate carboxypeptidase II is overexpressed in most of the cases of prostate cancer including metastases. This makes it exceptionally interesting for tumor targeting. The development of the ligand PSMA-11, radiolabeled with the positron emitter ⁶⁸Ga, has quickly become the „gold standard“ for nuclear investigations of metastasised prostate cancer and largely replaced choline-based radiotracers such as ¹¹C- or ¹⁸F-cholin. In spite of the success of ⁶⁸Ga-PSMA-11 one should not forget, that gamma cameras are more widely available than PET scanners. Moreover, technetium-99 m (^99 mTc) is still the most often used radionuclide in nuclear medicine. This review summarises the evolution and current status of ^99 mTc radiotracers targeting PSMA.

Results: Over the past years, diverse research groups have developed ligands that bind to PSMA and can be labeled with ^99 mTc. A series of ^99 mTc-PSMA ligands has already been tested clinically. Three main parameters have been varied and investigated by several groups: 1) The chelator and oxidation state of the ^99 mTc-metal core; 2) the linker entity between the ^99 mTc-complex and the PSMA-binding entity; and 3) finally, the PSMA-biding entity. Simple tetradentate derivatives of MAG₃ (mercaptoacetylglycine) but also hydrazinonicotinic acid (HYNIC) were used for the coordination of ^99 mTc in the oxidation state + V. The ^99 mTc-tricarbonyl core was employed for the coordination of the metal in its oxidation state + I using tridentate chelators. Linker entities of different lengths and with or without aromatic side chains were developed and tested. The radioligands with more hydrophilic chelators and linker entities showed commonly faster pharmacokinetic profiles. Radioligands with aromatic side chains in the linker entity showed increased tumor uptake and retention. Only slight differences were found with regard to the PSMA-binding sites when glutamate-urea-glutamate or glutamate-urea-lysine was used. The alternative PSMA-binding entity (2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)-methyl]pentan-1,5-dioic acid (GPI) has also been functionalised for radiolabeling with ^99 mTc, however, ^99 mTc-GPI derivatives have not reached clinical application yet.

Conclusions: Based on the current clinical results, it is still not clear which ^99 mTc-radioligand will evolve for routine application in clinics. For this purpose more extended and, in particular, comparative studies (with the gold-standard ⁶⁸Ga-PSMA-11) will be necessary. Undoubtedly, ^99 mTc-based PSMA-ligands will enter clinical routine in future.

Schlüsselwörter

^99 mTc - PSMA - SPECT - diagnostische Bildgebung - Prostatakrebs

Keywords

^99 mTc - PSMA - SPECT - diagnostic imaging - prostate cancer

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