In vitro and in vivo evaluation of the bifunctional chelator NODIA-Me in combination with a prostate-specific membrane antigen targeting vector

Läppchen, Tilman; Kiefer, Yvonne; Holland, Jason P.; Bartholomä, Mark D. (2018). In vitro and in vivo evaluation of the bifunctional chelator NODIA-Me in combination with a prostate-specific membrane antigen targeting vector. Nuclear medicine and biology, 60, pp. 45-54. Elsevier 10.1016/j.nucmedbio.2018.03.002

[img] Text
1-s2.0-S0969805117302676-main.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

INTRODUCTION: We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three five-membered azaheterocyclic arms for complexation of the PET nuclides gallium-68 and copper-64. The main objective of this study was to evaluate the stability and pharmacokinetics of 68Ga- and 64Cu-complexes of the bifunctional chelator NODIA-Me 1 covalently bound to a PSMA targeting vector in vivo. METHODS: NODIA-Me 1 was conjugated to the PSMA targeting Glu-NH-CO-NH-Lys moiety to give the bioconjugate NODIA-Me-NaI-Ahx-PSMA 4. The stability of [68Ga]4 and [64Cu]4 was assessed in vitro by serum stability studies. The PSMA binding affinity was determined in competitive cell experiments in LNCaP cells using 68Ga-PSMA-HBED-CC as radioligand. The stability and pharmacokinetics of [68Ga]4 and [64Cu]4 was evaluated by PET imaging and ex vivo biodistribution studies in mice bearing subcutaneous LNCaP tumors. RESULTS: In human serum, [68Ga]4 and [64Cu]4 remained intact to 85% (3 h) and 92% (24 h), respectively. Nature of the metal chelate influenced PSMA binding affinity with IC50 of 233 ± 10 nM for uncomplexed 4, 681 ± 7 nM for Cu-4 and 176 ± 10 nM for Ga-4. In animal studies, [68Ga]4 and [64Cu]4 revealed low uptake (≤1% IA g-1) in the majority of organs. Kidney uptake at 1 h p.i. was 6.28 ± 0.92% IA g-1 and 4.96 ± 0.79% IA g-1 and specific tumor uptake was 1.33 ± 0.46% IA g-1 and 2.15 ± 0.38% IA g-1 for [68Ga]4 and [64Cu]4, respectively. CONCLUSION: The bifunctional chelator NODIA-Me 1 was successfully conjugated to a PSMA targeting moiety. In small-animal PET imaging and ex vivo biodistribution studies, 68Ga- and 64Cu-labelled conjugates specifically delineated PSMA-positive LNCaP tumors and exhibited rapid renal clearance from non-target tissues with no significant demetallation/transchelation in vivo. The results support further development of this novel chelating platform for production of 68Ga- and 64Cu-labelled radiopharmaceuticals.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Läppchen, Tilman


600 Technology > 610 Medicine & health








Sabine Lanz

Date Deposited:

01 Feb 2019 14:44

Last Modified:

24 Oct 2019 22:29

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Bifunctional chelator; Copper-64; Gallium-68; PET imaging; Prostate-specific membrane antigen (PSMA)




Actions (login required)

Edit item Edit item
Provide Feedback