Synthesis and Biological Evaluation of a New Type of <sup>99m</sup>Technetium-Labeled Fatty Acid for Myocardial Metabolism Imaging

With the aim of developing 99mTc-labeled fatty acids intended for myocardial metabolism imaging we report herein the synthesis and characterization of two novel derivatives of undecanonoic and hexadecanonoic acid that have been functionalized at the ω-site by cysteine through the formation of a thioether bond (Cys–FA11 and Cys–FA16). Equimolar amounts of each ligand and the [NEt4]2[Re(CO)3Br3] precursor generated the respective hexacoordinated neutral complexes in which the ligand coordinated to the metal through the SNO donor system of cysteine. The rhenium complexes were characterized by elemental analysis, IR and NMR spectroscopies. The analogous technetium-99m complexes, 99mTc–Cys–FA11 and 99mTc–Cys–FA16 were prepared by incubation of the ligand with the precursor [99mTc(CO)3(H2O)3]+ (radiochemical yield ≥98%). Their structure was established by comparative HPLC techniques. In vivo studies in mice showed high initial heart uptake for both 99mTc complexes (7.4 ± 0.53 and 7.07 ± 0.73 percentage of injected dose (%ID)/g at 1 min post injection. Rapid clearance (0.60 ± 0.02 %ID/g) was observed for 99mTc–Cys–FA11 while the clearance of the longer fatty acid 99mTc–Cys–FA16 was slower (2.31 ± 0.09 %ID/g at 15 min p.i.). Metabolite analysis study indicated that complexes were catabolized through the β-oxidation process.

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“…Selected examples of 99m Tc-labelled fatty acids in different oxidation states [21,22,29,32,35,37,38].…”

Section: Methodsmentioning

confidence: 99%

Cysteine Derivatized 99mTc-Labelled Fatty Acids as β-Oxidation Markers

et al. 2019

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“…Several 99m Tc labeled fatty acids following different 99m Tc chemistries viz. oxotechnetium (V) core ([ 99m Tc = O] 3+ ), 11 nitrido core ([ 99m TcN(PNP)] 2+ ), 12,13 99m Tc-4 + 1 mixed ligand approach, 14,15 tricarbonyl core ([ 99m Tc(CO) 3 (H 2 O) 3 ] + ), 16,17 cyclopentadienyl tricarbonyl technetium ( 99m Tc-CpTT) core, [18][19][20] and 99m Tc-HYNIC, 21 were developed and evaluated in past but all lacked favorable characteristics for in vivo imaging. 99m Tc cores/ BFCAs alter in vivo pharmacokinetic behavior of fatty acids of identical chain lengths.…”

Section: Introductionmentioning

confidence: 99%

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

Das

Mathur

Sakhare

et al. 2018

Labelled Comp Radiopharmac

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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.

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“…Several FA radiotracers with different 99m Tc‐cores and complex structures, such as 99m Tc‐3 + 1 (3 = tridentate S,E,S donor ligand cap [S = thiol S,E = thioether S, ether O or substituted N], 1 = monodentate mercaptide), 99m Tc‐4 + 1 (4 = tripodal tetradentate, 1 = monodentate), [ 99m Tc(CO) 3 (H 2 O) 3 ] + , 99m Tc‐O, [ 99m TcN(PNP)] 2+ , and 99m Tc(CO) 3 ‐cyclopentadienyl ( 99m Tc‐CpTT) have been reported. However, poor myocardial accumulation and short retention of the 99m Tc‐labeled FAs may be the major biological factors negatively affecting their further application. Therefore, efforts have been made to develop 99m Tc‐labeled FA analogues with the advantages of high heart to liver ratio, quick blood washout, low‐lungs uptake, and long myocardial retention.…”

Section: Introductionmentioning

confidence: 99%

Initial evaluation of ^99m Tc-tricarbonyl-cyclopentadienyl fatty acids derivatives as SPECT tracers for myocardium

Liu

Wang

et al. 2017

J. Label Compd. Radiopharm

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Fatty acids are myocardial metabolic agent for detecting myocardial ischemia and infraction. However, no Tc-labeled fatty acids had potential use in clinical practice. In this study, Tc-CpTT-10-oxo-para-PPA (1d), Tc-CpTT-11-oxo-para-PPA (2d), Tc-CpTT-12-oxo-para-PPA (3d), Tc-CpTT-11-oxo-ortho-PPA (4d), and Tc-CpTT-11-oxo-meta-PPA (5d) were synthesized by a double ligand transfer reaction, and their biological behaviors were investigated. Compound 2d achieved good heart to blood ratio (3.39 at 5 min after intravenous), and 2d showed high-heart uptake of 6.20% ID/g at 5 minutes after injection. Compound 3d displayed a prolonged retention in the myocardium (1.43% ID/g at 60 min after injection). Radioactivity accumulation in the lungs, spleen, and blood was eliminated rapidly. In vivo, metabolite analysis presented that compound 6d may be metabolite of 2d through β-oxidation in tissue. Unfortunately, the biodistribution studies of 1d, 2d, 3d, 4d, and 5d showed fast heart clearance and poor heart to liver ratios, which suggested that the 5 Tc-labeled fatty acid analogues cannot be used for diagnosis.

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Synthesis and Biological Evaluation of a New Type of ^99mTechnetium-Labeled Fatty Acid for Myocardial Metabolism Imaging

Cited by 43 publications

References 21 publications

Cysteine Derivatized 99mTc-Labelled Fatty Acids as β-Oxidation Markers

Cysteine Derivatized 99mTc-Labelled Fatty Acids as β-Oxidation Markers

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

Initial evaluation of ^99m Tc-tricarbonyl-cyclopentadienyl fatty acids derivatives as SPECT tracers for myocardium

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Synthesis and Biological Evaluation of a New Type of 99mTechnetium-Labeled Fatty Acid for Myocardial Metabolism Imaging

Cited by 43 publications

References 21 publications

Cysteine Derivatized 99mTc-Labelled Fatty Acids as β-Oxidation Markers

Cysteine Derivatized 99mTc-Labelled Fatty Acids as β-Oxidation Markers

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

Initial evaluation of 99m Tc-tricarbonyl-cyclopentadienyl fatty acids derivatives as SPECT tracers for myocardium

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Synthesis and Biological Evaluation of a New Type of ^99mTechnetium-Labeled Fatty Acid for Myocardial Metabolism Imaging

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

Initial evaluation of ^99m Tc-tricarbonyl-cyclopentadienyl fatty acids derivatives as SPECT tracers for myocardium