Synthesis and biodistribution studies of ^99mTc labeled fatty acid derivatives prepared via “Click approach” for potential use in cardiac imaging

Abstract

I-Iodophenylpentadecanoic acid (IPPA) is a metabolic agent used in nuclear medicine for diagnosis of myocardial defects. Efforts are underway worldwide to develop a Tc substitute of the above radiopharmaceutical for the aforementioned application. Herein, we report synthesis and biodistribution studies of Tc labeled fatty acids (8, 11, and 15 carbons) obtained via "click chemistry" for its potential use in myocardial imaging. ω-Bromo fatty acids (8C/11C/15C) were synthetically modified at bromo terminal to introduce a heterocyclic triazole with glycine sidearm in a five step procedure. Modified fatty acids were subsequently radiolabeled with preformed [ Tc(CO) ] synthon to yield the desired fatty acid complexes which were evaluated in Swiss mice. All the radiolabeled complexes were obtained with radiochemical purities >80%, as characterized by HPLC. Biodistribution studies of all three complexes in Swiss mice showed myocardial uptake of ~6-9% ID/g at 2 minutes post-injection, close to I-IPPA (~9% ID/g). Complexes exhibited significant retention in the myocardium up to 30 minutes (~1% ID/g) but were lower to the standard agent (~7% ID/g). Similar uptake of activity in myocardium for the newly synthesized complexes in comparison to I-IPPA along with favorable in vivo pharmacokinetics merits potential for the present "click" design of complexes for myocardial imaging.

Click Chemistry and Radiochemistry: An Update

“…In this technique, a CuAAC ligation between azide- and alkyne-bearing substrates creates a bespoke chelator in which the 1,2,3-triazole participates in the coordination of the radiometal as a ligand with both σ-donor and π-acceptor character. This approachdubbed “Click-to-Chelate” when it was first reported in 2006has most famously been used to create tridentate chelators for radiolabeling with Tc­(I) cores like [ 99m Tc]­[Tc­(CO) 3 (H 2 O) 3 ] + but has been employed with Re­(I) synthons as well. − Recently, Mindt and co-workers used this approach to synthesize 99m Tc-labeled probes in which the radiometal is sequestered by a tripodal N 2 O-based architecture created via the reaction of N α -propargyl lysine with an azide-bearing vector (Figure A). , Others have taken a similar approach to creating probes in which 99m Tc­(I) is coordinated by N 2 O- and NSO-containing coordination structures, most notably a multimodal, PSMA-targeted theranostic designed to facilitate both SPECT imaging and photodynamic therapy. ,− In yet another example, Erfani et al created a 99m Tc-labeled agent for the visualization of 5HT 1A serotonin receptors in the brain by clicking together 2-ethynylpyridine and an azide derived from 1-(2-methoxyphenyl)­piperazine (Figure B). The 99m Tc-labeled probe displayed brain uptake of 1.4 ± 0.1 %ID/g 15 min post-administration with hotspots in the 5HT 1A -active hippocampus .…”