Quantification of fatty acid uptake with [18F]FTHA PET


Long-chain free fatty acids (FFAs) are transported in blood bound to albumin. Passive diffusion and facilitated transport via specific membrane-associated and cytosolic fatty acid binding proteins (FABP) are involved in entry into the cells (Frohnert and Bernlohr, 2000). In cells acyl-CoA synthetase (ACS) activates FFA to the fatty acyl-CoA derivative. This is necessary for the major metabolic pathways of FFA metabolism, including β-oxidation and esterification, and therefore net flux through this reaction represents total fatty acid utilization.

The long-chain fatty acid analogue 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA, DeGrado et al., 1991) enters the cells by the same mechanism as natural fatty acids and undergoes partial metabolism in mitochondria before being trapped because of its sulphur atom. Tissue accumulation of 18F represents total fatty acid utilization, including both β-oxidation and storage as glycerol esters and phospholipids (Guiducci et al., 2007). [18F]FTHA production can be automated, according to GMP (Savisto et al., 2018).

[18F]FTHA is the most used PET radiotracer for assessing fatty acid utilization. More specific fatty acid oxidation tracers have been developed, including [18F]FTO (DeGrado et al., 2010 and 2018) and 7-[18F]FTO (Murakami et al., 2023)..

[18F]FTHA net influx rate (Ki) or fractional uptake rate (FUR) must be multiplied by FFA concentration in (arterial) plasma to calculate the FFA uptake (utilization) rate. There is a 100-fold range of possible FFA plasma concentrations. To account for the different kinetics of [18F]FTHA and palmitate and other FFAs, the rate index should also be be divided by "lumped constant" (LC).

Fatty acids in plasma and blood

FFAs in plasma are normally more than 99.99% bound to circulating plasma proteins. Although FFA transport across erythrocyte plasma membranes is rapid, the high plasma protein binding leads to negligible FFA concentration inside the erythrocytes. Covalently bound fatty acids in erythrocytes slowly exchange (halflife 30 min or more) with fatty acids in plasma.

Measured [18F]FTHA blood concentration data can be converted to represent plasma curve by assuming that all radioactivity resides in the plasma, using haematocrit.

Metabolite correction of plasma TAC

Label-carrying metabolites of [18F]FTHA appear fast in the plasma, and 30 min after injection only about 20-30% of the total radioactivity is due to the parent radiotracer. Metabolism rate may differ between study groups (Supplemental Figure 1 by Labbé et al., 2011a). In pigs, 18F-labelled triglycerides are detectable in plasma already after 10 min, and both the amount and fraction is increasing by time (Guiducci et al., 2007).

Fluoride ([18F]F-) is one of the metabolites, which may be seen as bone uptake in the late images. Fluoride distributes from plasma to other tissues, too, which may affect quantitation in case the FFA uptake is relatively low.

Plasma curves must be corrected for metabolites before it is used as input function. A Hill-type function can be fitted to measured plasma parent fractions.


Multiple-time graphical analysis for irreversible uptake (Patlak plot) with metabolite corrected plasma input can be used to measure FFA oxidation and storage rate in the fasting state (Iozzo et al., 2003a; Hannukainen et al., 2007; Viljanen et al., 2009a; Immonen, et al. 2017). The uptake kinetics of [18F]FTHA are not fully irreversible in the liver, but the slight downward curvature of Patlak plots does not prevent line-fitting to plot data measured 10-32 min after injection (Iozzo et al., 2003a). Uptake rate can be calculated regionally or a Ki image can be computed. If only static image or late scan with few time frames is available, FUR (retention index) image can be computed.

[18F]FTHA has also been administered orally to study organ-specific dietary fatty-acid uptake (Labbé et al., 2011b).

Skeletal muscle

Quantification methods for skeletal muscle have been described by Mäki et al (1998) and Turpeinen et al (1999).

Using [18F]FTHA and Patlak graphical analysis has been validated in a pig study, suggesting that in skeletal muscle [18F]FTHA depicts FFA uptake, but not specifically β-oxidation (Takala et al., 2002). [18F]FTHA uptake has been quantified also from a single late PET frame (Hannukainen et al., 2006 and 2007).

Regulation of fatty acid utilization

It is not known what exactly are the roles of passive diffusion and facilitated transport via specific membrane-associated and cytosolic fatty acid binding proteins in entry into cells; at least in certain conditions the fatty acid uptake displays saturation kinetics. Regulation of fatty acid utilization in skeletal muscle during exercise may lie mainly within the entrance into the mitochondria or metabolism within the mitochondria (Kiens and Roepstorff, 2003), although there is evidence that plasmalemmal fatty acid transport in heart and skeletal muscle is regulated for example by contraction, insulin, and leptin (Bonen et al., 2003). It has been shown in humans that a marked storage of lipids in skeletal muscle can be increased by the combination of hyperinsulinemia and elevation of circulating FFAs, but not by one of these conditions alone (Brechtel et al., 2001).

Adipose tissue

Entry of long-chain fatty acids into adipocytes is mediated by facilitated transport. [18F]FTHA can be used to measure FFA uptake in white adipose tissue (Bucci et al., 2015; Dadson et al., 2017) and brown adipose tissue (Blondin et al., 2017).


Experimental validation studies have shown correlation between trapping of [18F]FTHA and fatty acid oxidation in myocardial muscle various conditions (Ebert et al., 1994; Stone et al., 1998; Takala et al., 2002). However, in hypoxic conditions of myocardium [18F]FTHA may not be optimal for measuring changes in β-oxidation (Renstrom et al., 1998).

Patlak plot has been used in human studies to calculate the [18F]FTHA net influx rate (Ki), and further by assuming LC=1, it has been used to estimate myocardial β-oxidation rate of long chain fatty acids without (Taylor et al., 2001; Wallhaus et al., 2001) or with (Ebert et al., 1994; Mäki et al. 1997, 1998; Takala et al., 1999 and 2002; Turpeinen et al., 1999; Hannukainen et al., 2007; Tuunanen et al., 2007; Viljanen et al., 2009b) plasma metabolite correction. In rodents the [18F]FTHA uptake is not irreversible (DeGrado et al., 1991), preventing the use of Patlak plot in strictly quantitative analysis; Huber et al. (2017) estimated changes in influx rates in rat models with Patlak plot, using as input function the blood curve derived from LV cavity without metabolite correction.


A good review on fatty acid incorporation in the brain is written by Robinson et al (1992).

The equilibrium unbound fraction of un-acylated palmitate in plasma is less than 0.007%, and fatty acid-albumin complex cannot cross the blood-brain barrier. Yet, in rat brain the single-pass extraction of palmitate is about 5%. This means that fatty acids must be released from albumin during the passage through capillaries, and therefore protein-bound fraction is not needed to quantify the fatty acid uptake in PET studies. Relatively low first-pass extraction also means that fatty acid uptake in the brain is independent of cerebral blood flow.

FUR method can be used in quantification of [18F]FTHA uptake rate in the brain (Karmi et al., 2010; Rebelos et al., 2020). Patlak plot has been used in human studies to calculate the [18F]FTHA net influx rate (Ki) and fatty acid uptake (Honkala et al., 2018).


FFA uptake rate in intestine (duodenum and jejunum) and colon has been measured using [18F]FTHA (Motiani et al., 2017; Koffert et al., 2018).

See also:


Bonen A, Benton CR, Campbell SE, Chabowski A, Clarke DC, Han X-X, Glatz JFC, Luiken JJFP. Plasmalemmal fatty acid transport is regulated in heart and skeletal muscle by contraction, insulin and leptin, and in obesity and diabetes. Acta Physiol. Scand. 2003; 178: 347-356. doi: 10.1046/j.1365-201X.2003.01157.x

Brechtel K, Dahl DB, Machann J, Bachmann OP, Wenzel I, Maier T, Claussen CD, Häring HU, Jacob S, Schick F. Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic 1H-MRS study. Magn Reson Med. 2001; 45:179-183. PMID: 11180422.

DeGrado TR, Coenen HH, Stocklin G. 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA): evaluation in mouse of a new probe of myocardial utilization of long chain fatty acids. J Nucl Med. 1991; 32(10): 1888-1896. doi: 1919727.

Ebert A, Herzog H, Stöcklin GL, Henrich MM, DeGrado TR, Coenen HH, Feinendegen LE. Kinetics of 14(R,S)-fluorine-18-fluoro-6-thia-heptadecanoic acid in normal human hearts at rest, during exercise and after dipyridamole injection. J Nucl Med. 1994; 35: 51-56. PMID: 8271060.

Frohnert BI, Bernlohr DA. Regulation of fatty acid transporters in mammalian cells. Progr Lipid Res. 2000; 39:83-107. doi: 10.1016/S0163-7827(99)00018-1.

Guiducci L, Grönroos T, Järvisalo MJ, Kiss J, Viljanen A, Naum AG, Viljanen T, Savunen T, Knuuti J, Ferrannini E, Salvadori PA, Nuutila P, Iozzo P. Biodistribution of the fatty acid analogue 18F-FTHA: plasma and tissue partitioning between lipid pools during fasting and hyperinsulinemia. J Nucl Med. 2007; 48(3): 455-462. PMID: 17332624.

Hannukainen JC, Nuutila P, Kaprio J, Heinonen OJ, Kujala UM, Janatuinen T, Rönnemaa T, Kapanen J, Haaparanta-Solin M, Viljanen T, Knuuti J, Kalliokoski KK. Relationship between local perfusion and FFA uptake in human skeletal muscle - no effect of increased physical activity and aerobic fitness. J Appl Physiol. 2006; 101(5):1303-1311. doi: 10.1152/japplphysiol.00012.2006.

Hannukainen JC, Nuutila P, Borra R, Kaprio J, Kujala UM, Janatuinen T, Heinonen OJ, Kapanen J, Viljanen T, Haaparanta M, Rönnemaa T, Parkkola R, Knuuti J, Kalliokoski KK. Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins. J Physiol. 2007; 578(Pt 1): 347-358. doi: 10.1113/jphysiol.2006.121368.

Honka H, Hannukainen JC, Tarkia M, Karlsson H, Saunavaara V, Salminen P, Soinio M, Mikkola K, Kudomi N, Oikonen V, Haaparanta-Solin M, Roivainen A, Parkkola R, Iozzo P, Nuutila P. Pancreatic metabolism, blood flow, and β-cell function in obese humans. J Clin Endocrinol Metab. 2014; 99(6): E981-E990. doi: 10.1210/jc.2013-4369.

Iozzo P, Turpeinen AK, Takala T, Oikonen V, Solin O, Ferrannini E, Nuutila P, Knuuti J. Liver uptake of free fatty acids in vivo in humans as determined with 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid and PET. Eur J Nucl Med Mol Imaging 2003a; 30: 1160-1164. doi: 10.1007/s00259-003-1215-0.

Iozzo P, Takala T, Oikonen V, Bergman J, Grönroos T, Ferrannini E, Nuutila P, Knuuti J. Effect of training status on regional disposal of circulating free fatty acids in the liver and skeletal muscle during physiological hyperinsulinemia. Diabetes Care 2004a; 27: 2127-2177. doi: 10.2337/diacare.27.9.2172.

Iozzo P, Turpeinen AK, Takala T, Oikonen V, Bergman J, Grönroos T, Ferrannini E, Nuutila P, Knuuti J. Defective liver disposal of free fatty acids in patients with impaired glucose tolerance. J Clin Endocrinol Metab. 2004b; 89: 3496-3502. doi: 10.1210/jc.2003-031142.

Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, Oikonen V, Kemppainen J, Viljanen T, Guiducci L, Haaparanta-Solin M, Någren K, Solin O, Nuutila P. Increased brain fatty acid uptake in metabolic syndrome. Diabetes 2010; 59: 2171-2177. doi: 10.2337/db09-0138.

Kiens B, Roepstorff C. Utilization of long-chain fatty acids in human skeletal muscle during exercise. Acta Physiol Scand 2003; 178: 391-396. doi: 10.1046/j.1365-201X.2003.01156.x.

Labbé SM, Croteau E, Grenier-Larouche T, Frisch F, Oullet R, Langlois R, Guérin B, Turcotte EE, Carpentier AC. Normal postprandial nonesterified fatty acid uptake in muscles despite increased circulating fatty acids in type 2 diabetes. Diabetes 2011a; 60: 408-415. doi: 10.2337/db10-0997.

Labbé SM, Grenier-Larouche T, Croteau E, Normand-Lauziere F, Frisch F, Ouellet R, Guérin B, Turcotte EE, Carpentier AC. Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography. Am J Physiol Endocrinol Metab. 2011b; 300:E445-E453. doi: 10.1152/ajpendo.00579.2010.

Mäki M, Haaparanta MT, Luotolahti MS, Nuutila P, Voipio-Pulkki LM, Bergman JR, Solin OH, Knuuti JM. Fatty acid uptake is preserved in chronically dysfunctional but viable myocardium. Am J Physiol 1997; 273: H2473-H2480. doi: 10.1152/ajpheart.1997.273.5.H2473.

Mäki MT, Haaparanta M, Nuutila P, Oikonen V, Luotolahti M, Eskola O, Knuuti JM. Free fatty acid uptake in the myocardium and skeletal muscle using fluorine-18-fluoro-6-thia-heptadecanoic acid. J Nucl Med 1998; 39(8): 1320-1327. PMID: 9708500.

Renstrom B, Rommelfanger S, Stone CK, DeGrado TR, Carlson KJ, Scarbrough E, Nickles RJ, Liedtke AJ, Holden JE. Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia. J Nucl Med 1998; 39: 1684-1689. PMID: 9776269.

Robinson PJ, Noronha J, DeGeorge JJ, Freed LM, Nariai T, Rapoport SI. A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res Brain Res Rev. 1992; 17(3): 187-214. doi: 10.1016/0165-0173(92)90016-F.

Savisto N, Viljanen T, Kokkomäki E, Bergman J, Solin O. Automated production of [18F]FTHA according to GMP. J Labelled Comp Radiopharm. 2018; 61(2): 84-93. doi: 10.1002/jlcr.3589.

Stone CK, Pooley RA, DeGrado TR, Renstrom B, Nickles RJ, Nellis SH, Liedtke AJ, Holden JE. Myocardial uptake of the fatty acid analog 14-fluorine-18-fluoro-6-thia-heptadecanoic acid in comparison to beta-oxidation rates by tritiated palmitate. J Nucl Med 1998a; 39: 1690-1696. PMID: 9776270.

Takala TO, Nuutila P, Katoh C, Luotolahti M, Bergman J, Mäki M, Oikonen V, Ruotsalainen U, Grönroos T, Haaparanta M, Kapanen J, Knuuti J. Myocardial blood flow, oxygen consumption, and fatty acid uptake in endurance athletes during insulin stimulation. Am J Physiol. 1999; 277: E585-E590. doi: 10.1152/ajpendo.1999.277.4.E585.

Takala TO, Nuutila P, Pulkki K, Oikonen V, Grönroos T, Savunen T, Vähäsilta T, Luotolahti M, Kallajoki M, Bergman J, Forsback S, Knuuti J. 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid as a tracer of free fatty acid uptake and oxidation in myocardium and skeletal muscle. Eur J Nucl Med. 2002; 29: 1617-1622. doi: 10.1007/s00259-002-0979-y.

Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure. J Nucl Med. 2001; 42(1): 55-62. PMID: 11197981.

Turpeinen AK, Takala TO, Nuutila P, Axelin T, Luotolahti M, Haaparanta M, Bergman J, Hämäläinen H, Iida H, Mäki M, Uusitupa MI, Knuuti J. Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Diabetes 1999; 48(6): 1245-1250. doi: 10.2337/diabetes.48.6.1245.

Tuunanen H, Kuusisto J, Toikka J, Jääskeläinen P, Marjamäki P, Peuhkurinen K, Viljanen T, Sipola P, Stolen KQ, Hannukainen J, Nuutila P, Laakso M, Knuuti J. Myocardial perfusion, oxidative metabolism, and free fatty acid uptake in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the α-tropomyosin gene: a positron emission tomography study. J Nucl Cardiol. 2007; 14(3): 354-365. doi: 10.1016/j.nuclcard.2006.12.329.

Viljanen APM, Iozzo P, Borra R, Kankaanpää M, Karmi A, Lautamäki R, Järvisalo M, Parkkola R, Rönnemaa T, Guiducci L, Lehtimäki T, Raitakari OT, Mari A, Nuutila P. Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. J Clin Endocrinol Metab. 2009; 94(1):50-55. doi: 10.1210/jc.2008-1689.

Viljanen APM, Karmi A, Borra R, Pärkkä JP, Lepomäki V, Parkkola R, Lautamäki R, Järvisalo M, Taittonen M, Rönnemaa T, Iozzo P, Knuuti J, Nuutila P, Raitakari OT. Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. Am J Cardiol. 2009b; 103: 1721-1726. doi: 10.1016/j.amjcard.2009.02.025.

Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001; 103(20): 2441-2446. PMID: 11369683.

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Updated at: 2023-05-11
Created at: 2005-10-19
Written by: Vesa Oikonen