Modified “4 + 1” Mixed Ligand Technetium-Labeled Fatty Acids for Myocardial Imaging: Evaluation of Myocardial Uptake and Biodistribution

Abstract

Our group previously synthesized 99m Tc-labeled fatty acids suitable for myocardial metabolism and flow imaging. In this set of experiments, 29 new analogues were synthesized according to the "4 + 1" mixed ligand approach with some specific differences. Conventional "4 + 1" 99m Tc-fatty acids are built in the sequence: Tc-chelate, alkyl chain, and carboxylic group. We developed compounds following a new design with the sequence: carboxylic group, alkyl chain, Tc-chelate, and lipophilic tail. Therefore, the 99m Tc-chelate was transferred to a more central position of the compound, aiming toward an improved myocardial profile and an accelerated liver clearance. In this context, several functional groups incorporated in the lipophilic tail section were tested to evaluate their influence on the compound's character. In addition to biodistribution studies in vivo, the myocardial first-pass extraction of the compounds was tested in an isolated Langendorff rat heart model. A satisfactory myocardial uptake of up to 20% of the injected dose (% ID) in the perfused heart and a fast liver clearance in vivo with only 0.29% ID/g at 60 min postinjection demonstrate that the induced molecular modifications affect the kinetics of 99m Tc-radiolabeled fatty acid compounds favorably. From the data set, rules for estimating the biodistribution of fatty acids tracers are deduced.

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

“…In all these approaches a chelating moiety has been incorporated into a fatty acid (Scheme 2). Ideally, the moiety should not interfere with the biological properties of the fatty acid allowing recognition by membrane and intracellular proteins [36]. However, the biodistribution studies of the 99m Tc-labelled fatty acids indicated mediocre myocardial uptake, rapid myocardial washout and poor heart/blood and heart/liver ratios when compared to the advantageous biodistribution patterns of the established radio-iodinated fatty acid tracers .…”

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

“…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.…”

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

“…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.…”