In vitro and in vivo evaluation of novel ligands for radioimmunotherapy

Chong, Hyun-Soon; Milenic, Diane E.; Garmestani, Kayhan; Brady, Erik D.; Arora, Hans; Pfiester, Candice; Brechbiel, Martin W.

doi:10.1016/j.nucmedbio.2006.03.004

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 4 , Pages 459-467, May 2006

In vitro and in vivo evaluation of novel ligands for radioimmunotherapy

Hyun-Soon Chong
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Chemistry Division, Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA
- Corresponding author. Chemistry Division, Biological, Chemical, and Physical Science Department, Illinois Institute of Technology, Chicago, IL 60616, USA. Tel.: +1 312 567 3235; fax: +1 312 567 3494.
Diane E. Milenic
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Kayhan Garmestani
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Erik D. Brady
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Hans Arora
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Candice Pfiester
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Martin W. Brechbiel
- Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

Received 22 December 2005; received in revised form 30 January 2006; accepted 7 March 2006. published online 02 May 2006.

Abstract

Novel ligands cis-2,6-bis[N,N-bis(carboxymethyl)aminomethyl]-1-piperidineacetic acid (PIP-DTPA), cis-[(1R,11S)-6,9,15-Tris-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadec-3-yl]-acetic acid (PIP-DOTA), cis-{2,7-bis-[bis-carboxymethyl-amino)-methyl]-azepan-1-yl}-acetic acid (AZEP-DTPA), [2-(4,7-bis-carboxymethyl-[1,4,7]triazacyclononan-1-yl-ethyl]-2-carbonylmethyl-amino]-tetraacetic acid (NETA) and [{4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA) are investigated as potential chelators of ¹⁷⁷Lu, ⁹⁰Y, ²¹²Pb and ²¹³Bi for radioimmunotherapy (RIT). The new ligands are radiolabeled with ¹⁷⁷Lu, ^86/88/90Y, ²⁰³Pb and ^205/6Bi, and in vitro stability and in vivo stability of the radiolabeled complexes are assessed in human serum and athymic mice, respectively. In vitro studies indicate that all radiolabeled complexes with the exception of ⁹⁰Y-AZEP-DTPA are stable in serum for 5–11 days. All new ligands examined herein are found to tightly hold ¹⁷⁷Lu in vivo. Piperidine-backboned DTPA (PIP-DTPA) complexes radiolabeled with all radioisotopes examined display excellent in vivo stability, that is, excretion without dissociation. The azepane-backboned DTPA derivative, AZEP-DTPA, appears ineffective in binding all but ¹⁷⁷Lu in vivo. NETA and NPTA radiolabeled with ⁸⁶Y or ¹⁷⁷Lu exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with ²⁰³Pb-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both ²⁰³Pb-PIP-DOTA and ^205/6Bi-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for ^205/6Bi but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind ²⁰³Pb and ^205/6Bi in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for ¹⁷⁷Lu and ⁹⁰Y. Serum stability and in vivo biodistribution results suggest PIP-DTPA as a potential chelating agent with broad applicability for use in ¹⁷⁷Lu, ⁹⁰Y, ²¹²Pb and ²¹³Bi RIT.