Synthesis and evaluation of radiogallium-labeled long-chain fatty acid derivatives as myocardial metabolic imaging agents

Abstract

Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart.

Synthesis and Evaluation of Radiogallium Labeled Bone-Imaging Probes Using Oligo-γ-Carboxy Glutamic Acid Peptides as Carriers to Bone

“…In fact, there were no differences in hydroxyapatite affinity and bone accumulation between 67 Ga-DOTA-( l -Asp) n and 67 Ga-DOTA-( d -Asp) n in our previous studies. , After the syntheses of HBED-CC-(Gla) n and HBED-CC-(Glu) n , 67 Ga labeling was performed. It is known that HBED-CC coordinates with 67/68 Ga with high radiochemical yields. , In this study, as we expected, [ 67 Ga]­Ga-HBED-CC-(Gla) n and [ 67 Ga]­Ga-HBED-CC-(Glu) n were also prepared with a high radiochemical purity without any purification. This finding was particularly interesting because clinical kits of these tracers for 68 Ga radiolabeling can be prepared easily for very convenient clinical use.…”

“…It is known that HBED-CC coordinates with 67/68 Ga with high radiochemical yields. 24,32 In this study, as we expected, [ 67 Ga]Ga-HBED-CC-(Gla) n and [ 67 Ga]Ga-HBED-CC-(Glu) n were also prepared with a high radiochemical purity without any purification. This finding was particularly interesting because clinical kits of these tracers for 68 Ga radiolabeling can be prepared easily for very convenient clinical use.…”

“…Therefore, superior peptide-based carriers to bone with a higher affinity have been required, and we hypothesized that (Gla) n peptides could be more effective carriers with a higher affinity for hydroxyapatite. Because the higher affinity of bisphosphonate for hydroxyapatite could be explained by the coordination structure with calcium in hydroxyapatite, a stable sixmembered chelate ring or five-membered chelate ring could be formed as cyclic First, we synthesized an Fmoc amino acid, Fmoc-Gla-(OtBu) 2 -OH, 31 and HBED-CC ligand, 24 respectively, as materials for solid-phase peptide synthesis of HBED-CC-(Gla) n . Although Fmoc-Gla(OtBu) 2 -OH was synthesized as a racemic mixture, it was used in the following peptide synthesis without optical resolution because the stereochemistry of the amino acid would not significantly affect the affinity for hydroxyapatite and bone accumulation, unlike the typical affinity of a peptide ligand for a protein receptor.…”

“…First, we synthesized an Fmoc amino acid, Fmoc-Gla­(OtBu) 2 -OH, and HBED-CC ligand, respectively, as materials for solid-phase peptide synthesis of HBED-CC-(Gla) n . Although Fmoc-Gla­(OtBu) 2 -OH was synthesized as a racemic mixture, it was used in the following peptide synthesis without optical resolution because the stereochemistry of the amino acid would not significantly affect the affinity for hydroxyapatite and bone accumulation, unlike the typical affinity of a peptide ligand for a protein receptor.…”

“…Thus, oligo-peptides of repeated γ-carboxy glutamic acid [(Gla) n ], which has a further carboxy group attached to the γ-position carbon of Gla, were expected to be a superior carrier to the bone. Additionally, N,N′ -bis-[2-hydroxy-5-(carboxyethyl)­benzyl] ethylenediamine- N,N′ -diacetic acid (HBED-CC) was chosen as a chelator for radiogallium because it had been reported that HBED-CC forms a stable radiogallium-complex with high radiochemical yields in a short reaction time. , To develop superior peptide-based bone-seeking radiopharmaceuticals and peptide-based carriers to bone, the study aim was to synthesize and evaluate Ga-HBED-CC-(Gla) n in vitro and in vivo in comparison with Ga-HBED-CC-glutamic acid (Glu) n as a control (Figure ). Although we are interested in 68 Ga ( t 1/2 = 68 min) for PET imaging, 67 Ga ( t 1/2 = 3.3 days) was used in this essential study as an alternative radionuclide because of its long half-life.…”