Synthesis, Cu(ii) complexation,⁶⁴Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms

Abstract

A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper (II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper (II) ion within each macrocycle’s cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with 64Cu at room temperature in less than 1 hour with specific activities >1mCi/μg. The in vivo behavior of both 64Cu-CB-TE2P and 64Cu-CB-TE1A1P were investigated through biodistribution studies using healthy, male, Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copper chelators including CB-TE2A, NOTA and Diamsar.

Preparation and Biological Evaluation of 64Cu Labeled Tyr3-Octreotate Using a Phosphonic Acid-Based Cross-Bridged Macrocyclic Chelator

“…An acid inertness study of Cu(II)-CBTE1A1P in 5 M HCl at 90 °C gave a half-life of 6.8 h, 9 which indicates significantly less stability under these conditions than Cu(II)-CB-TE2A (half-life = 154 h). 22 This discrepancy can be explained by the possibility that conjugation of CB-TE1A1P to Y3-TATE improves the stability of Cu-CB-TE1A1P complex, or that the acid stability studies are not highly accurate for predicting in vivo behavior.…”

“…Ferdani et al recently reported the synthesis and 64 Cu radiolabeling of a monocarboxylate monophosphonate chelator, CB-TE1A1P (11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid). 9 64 Cu-CB-TE1A1P can be prepared at room temperature and was shown to have high in vivo stability in normal rats.…”

Synthesis and Evaluation of New Generation Cross-Bridged Bifunctional Chelator for 64Cu Radiotracers

“…CB-TE1A1P shows good properties as a BFC; importantly, it can be radiolabeled with 64 Cu ions at room temperature and has sufficient Cu-chelator stability. 20 This work triggered further structural modifications of CB-TE1A1P Scheme 1. Synthesis Scheme of PCB-TE1A1P a a (a) (i) 1,3-Propanediol di-p-tosylate, K 2 CO 3 , toluene, reflux 2 d, (ii) 20% NaOH, room temperature, 4 h, (69%), (b) 20% Pd(OH) 2 , CH 3 COOH, room temperature, overnight (99%), (c) paraformaldehyde, P(OEt) 3 , CHCl 3 , room temperature, 3−4 d, (60%), (d) tert-butyl bromoacetate, K 2 CO 3 , CHCl 3 , room temperature, 3−4 d, (90%), and (e) 6 M HCl, reflux, 10 h (70%).…”

Phosphonate Pendant Armed Propylene Cross-Bridged Cyclam: Synthesis and Evaluation as a Chelator for Cu-64

“…After acid decomplexation of Cu-PCB-TE2P in 5 M HCl at 90°C, it did not show any change in absorption, even after 48 h, which strongly indicated that Cu-PCB-TE2P was highly stable under these conditions and suggested that harsher conditions were required for Cu-decomplexation. In comparison with the propylene cross-bridged chelators, ethylene crossbridged chelators showed rapid degradation under the same conditions (5 M HCl at 90°C), and the half-lives of CB-TE2P and CB-TE1A1P were 3.8 and 6.8 h, respectively 21 (Supporting Information Table S1). …”

“…15−19 To take advantage of fast metal binding kinetics, cross-bridged BFCs having a phosphonate pendant arm (CB-TE2P and CB-TE1A1P) have been introduced. 20,21 Chelators CB-TE2P and CB-TE1A1P were radiolabeled with 64 Cu at room temperature. Unfortunately, the advantages of the changed pendant arm were overshadowed by decreased Cucomplex stability.…”