Molecular imaging of reduced renal uptake of radiolabelled [DOTA⁰,Tyr³]octreotate by the combination of lysine and Gelofusine in rats^[*]

Summary

Aim: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, kidney uptake of radiolabelled compound is the major dose-limiting factor. We studied the effects of Gelofusine (20 mg) and lysine (100 mg) and the combination of both after injection of therapeutic doses of radiolabelled [DOTA⁰,Tyr³]octreotate (60 MBq ¹¹¹In or 555 MBq ¹⁷⁷Lu labelled to 15 μg peptide) in male Lewis rats. Methods: Kidney uptake was measured by single photon emission computed tomography (SPECT) scans with a four-headed multi-pinhole camera (NanoSPECT) at 24 h, 5 and 7 days p. i. and was quantified by volume of interest analysis. For validation the activity concentration in the dissected kidneys was also determined ex vivo using a gamma counter and a dose calibrator. Results: Gelofusine and lysine both reduced kidney uptake of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate significantly by about 40% at all time points. The combination of Gelo - fusine and lysine resulted in a 62% inhibition of kidney uptake (p < 0.01 vs. lysine alone). A weak but significant dose-response relationship for Gelofusine, but not for lysine, was found. In a study with [¹¹¹In-DOTA⁰,Tyr³]octreotate, conclusions drawn from NanoSPECT data were confirmed by biodistribution data. Conclusions: We conclude that rat kidney uptake of radiolabelled somatostatin analogues can be monitored for a longer period in the same animal using animal SPECT. Gelofusine and lysine had equal potential to reduce kidney uptake of therapeutic doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. The combination of these compounds caused a significantly larger reduction than lysine or Gelofusine alone and may therefore offer new possibilities in PRRT. The NanoSPECT data were validated by standard biodistribution experiments.

Zusammenfassung

Ziel: Bei der Peptidrezeptor-Radionuklidtherapie (PRRT) mit radioaktiv markierten Somatostatinanaloga ist die Nierenaufnahme der wesentliche dosislimitierende Faktor. Wir untersuchten den Einfluss von Gelofusin (20 mg), Lysin (100 mg) und der Kombination von beiden auf die Nierenaufnahme nach Injektion von therapeutischen Dosen [DOTA⁰,Tyr³]- Octreotat (15 μg markiert mit 60 MBq ¹¹¹In oder 555 MBq ¹⁷⁷Lu) in Lewis-Ratten. Methoden: Die Nierenaufnahme wurde mit einer NanoSPECT-Kamera (Vierkopf- Multipinhole-SPECT) 24 h sowie 5 and 7 Tage p.i. gemessen. Die Nierenaufnahme wurde mit Hilfe einer VOI (volume of interest) Analyse berechnet. Zur weiteren Validierung der Methode wurde die in den Nieren gespeicherte Aktivitat nach Dissektion ex vivo mit einem Gammacounter gemessen. Resultate: Sowohl Gelofusin als auch Lysin reduzieren die Nierenaufnahme von [¹⁷⁷Lu-DOTA⁰,Tyr³]- Octreotat signifikant um ca. 40% zu allen gemessenen Zeitpunkten. Die Kombination von Gelofusin und Lysin reduzierte die Nierenaufnahme um bis zu 62% (p < 0,01 vs. Lysin). Eine mittlere statistisch signifikante Dosis-Wirkungskorrelation wurde fur Gelofusin gefunden, nicht jedoch fur Lysin. Die mit Hilfe der NanoSPECT gemessene Nierenaufnahme von [¹¹¹In-DOTA⁰,Tyr³]Octreotat wurde durch die Biodistributionsdaten bestatigt. Schlussfolgerung: Wie durch die Biodistributionsdaten bestatigt, zeigen unsere Ergebnisse, dass die Nierenaufnahme radioaktiv markierter Somatostatinanaloga mit SPECT verlasslich in einzelnen Tieren uber langere Zeitraume hinweg gemessen werden kann. Gelofusin und Lysin hemmen die Nierenaufnahme von [¹⁷⁷Lu-DOTA⁰,Tyr³]-Octreotat vergleichbar effizient. Durch Kombination beider Stoffe kann die Nierenaufnahme radioaktiv markierter Somatostatinanaloga weiter vermindert werden, was die Applikation von deutlicher hoheren Dosen bei der PRRT ermoglichen konnte.

Keywords

Molecular imaging - somatostatin analogues - kidney - Gelofusine - lysine - NanoSPECT

Schlüsselwörter

Molekulare Bildgebung - Somatostatinanaloga - Niere - Gelofusine - Lysin - NanoSPECT

^* Part of this work was presented at the 18th Meeting of the International Research group in Immuno-Scintigraphy and Therapy, London, UK; July 6–8 2006.

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