⁶⁸Ga labeled fatty acids for cardiac metabolic imaging: Influence of different bifunctional chelators

Development of ⁶⁸Ga labeled fatty acids is of immense interest due to the availability of ⁶⁸Ga through a generator and its superiority over SPECT based tracers in carrying out dynamic imaging on a PET scanner. Our present work explores the influence of different chelators on the cardiac uptake and pharmacokinetics of the ⁶⁸Ga-labeled fatty acids. Two new ⁶⁸Ga labeled fatty acids were synthesized by conjugation of 11-aminoundecanoic acid with the bifunctional chelators (BFCs) viz. p-SCN-Bn-DTPA (S-2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid) and p-SCN-Bn-NODAGA (S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) and their comparison was carried out with the previously reported ⁶⁸Ga-NOTA-undecanoic acid. Both the conjugates were radiolabeled with ⁶⁸Ga in high yields and purities (>95%). Their formation was established by preparation and characterization of their inactive analogs with ^natGa at macroscopic levels. Biodistribution studies of the complexes in Swiss mice showed lower initial myocardial uptake for ⁶⁸Ga-NODAGA-undecanoic acid (3.8±0.6%ID/g) and ⁶⁸Ga-DTPA-undecanoic acid (1.3±0.5%ID/g) complexes in comparison to previously reported ⁶⁸Ga-NOTA-undecanoic acid complex (7.4±2.8%ID/g) at 2min p.i. However, significant retention of the tracer in the myocardium was observed in the case of ⁶⁸Ga-NODAGA-undecanoic complex, which led to improved heart/non-target ratios of the complex over time in comparison to the other ⁶⁸Ga complexes. Similarly, the DTPA complex exhibited increased washout from the liver in comparison to other ⁶⁸Ga derivatives. The β oxidation mechanism in myocytes was investigated by isolating the myocardial extract post intravenous injection of the respective ⁶⁸Ga complexes and analyzing them by radio-HPLC, which showed metabolic transformation of the parent fatty acid complex peak in all the three complexes. This study has provided an insight into the design characteristics of ⁶⁸Ga labeled fatty acids to achieve the desired myocardial imaging characteristics.