Synthesis, characterization and structure-activity relationships of gallium, indium, and copper-labeled radio-pharmaceuticals for myocardial imaging with PET

Shiaw-Pyng Wey, Purdue University

Abstract

The development of radiopharmaceuticals labeled with positron-emitting $\sp{68}$Ga, obtained from a long-lived $\sp{68}$Ge/$\sp{68}$Ga generator system, could facilitate more widespread use of positron emission tomography (PET) in diagnostic imaging. Monocationic gallium complexes with hexadentate bis(salicylaldimine) ligands derived from $N,N\sp\prime$-bis(3-aminopropyl)ethylenediamine (BAPEN) have been found to provide the desired myocardial uptake and retention of radiotracers in animal models. Attempts to improve the myocardial uptake and heart-to-background ratios have been undertaken with studies on 22 gallium complexes structurally related to the reported lead compound, Ga(III) (bis(4,6-MeO$\sb2$sal)BAPEN) $\sp+$. By screening in the rat model, the results indicate: (1) ligand modification by introducing methyl groups into the propylene fragment of the BAPEN backbone significantly improves the biological properties of radiotracers; (2) the lipophilicity increases produced by introducing long-chain substituents onto the aromatic rings fail to improve the biological behavior of these tracers; and (3) 3-MeO-substitution of the aromatic rings consistently results in tracers that exhibit superior heart-to-background ratios relative to other aromatic ring modifications. These results led to intensive studies of new hexadentate Schiff-base ligands derived from alkyl-derivatized linear tetraamines. By converting the central secondary amines to N-methyl-substituted tertiary amines and combining the 3-MeO aromatic ring substitution, the resulting $\sp{67}$Ga (bis(3-MeOsal)-$N,N\sp\prime$-DMBAPEN) $\sp+$ complex was found to afford the best myocardial uptake seen with this class of compounds along with superb heart-to-liver ratios in the rat model. A series of seven cationic $\sp{111}$In complexes with hexadentate bis(salicylaldimine) ligands were also prepared and screened in the rat model. Like their $\sp{67}$Ga analogs, these $\sp{111}$In complexes were found to consistently afford significant myocardial uptake and retention of tracer following intravenous injection. A novel dithiadioxime complex of copper(II), chloro (3,3$\sp\prime $-(1,3-propanedithia)bis(3-methyl-2-butanone oximato)(1-)- ($S,S\sp\prime,N,N\sp\prime$) copper(II) monohydrate, was also prepared, characterized by X-ray crystallography, and radiolabeled with $\sp{67}$Cu. The $\sp{67}$Cu-dithiadioxime complex is stable in ethanol solution but appears to decompose upon dilution with normal saline.

Degree

Ph.D.

Advisors

Green, Purdue University.

Subject Area

Pharmaceuticals|Pharmacology

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