Validation of 3-[11C]-OHB

Background:

Ketone bodies consists of 3-hydroxybutyrat, acetoacetate, and acetone. They are produced in the liver at high levels of fatty acids, and act as an important source of energy for the heart, brain and skeletal muscle during fasting. Energy production by ketone metabolism is less oxygen-intensive than both glucose and fatty acid metabolism, and ketone substances can therefore be a highly energy-efficient substrate. Insulin resistant individuals as well as people with heart disease have difficulty utilising glucose in the heart due to the insulin resistant condition and are therefore dependent on other energy sources such as free fatty acids and ketones. Because ketones are oxygen sparing compared to fatty acids, interventions that increase the level of ketone bodies can potentially reduce the heart's need for oxygen in patients with narrowed coronary arteries. This has led to an increased focus on the potential of ketone bodies in the treatment of a number of diseases, including especially cardiovascular disease.

Our group has shown that ketone bodies are efficiently absorbed by the heart despite maximal stimulation with insulin and glucose. In the study, healthy subjects increased the level of circulating ketone bodies to approximately 4 millimolar with a continuous ketone infusion, which resulted in a 50% reduction in cardiac glucose consumption. Since the consumption of free fatty acids in the experiment was unchanged and the overall work of the heart was the same, up to 50% of the heart's energy consumption was thus covered by ketone bodies. In addition, the high levels of ketone bodies led to a marked increase in the blood flow to the heart, which could potentially further benefit patients with narrowed coronary arteries

PET/CT is a functional and non-invasive imaging modality that is well established in oncological staging and treatment monitoring. The technique is also suitable for tracking the fate of metabolites non-invasively, as most substrates or metabolites can be labeled by a suitable PET isotope. PET has sufficient spatial and temporal resolution to enable direct quantification of e.g. uptake and oxidation rates and has been successfully used by our department to assess heart efficiency, oxygen consumption and fatty acid metabolism.

Purpose With this study, the investigators want to determine the metabolism of ketone bodies in healthy individuals and validate a newly developed ketone PET tracer for use in humans called 3-[11C]-OHB. Previous studies conducted by our and others' groups have only been able to indirectly estimate the uptake of ketone bodies into the heart. With 3-[11C]-OHB, the investigators will be able to directly measure tissue-specific ketone uptake, both after intravenous and oral administration.

Ihe investigators will apply state-of-the-science PET/CT tracer techniques and well-established models for estimating ketone metabolism (kinetics) and the radiation exposure of the tracer. Implementation of the 11C-3-OHB tracer in the future will allow the investigators to more directly estimate the impact of different levels of ketone bodies on organ functions, not least in the heart.

In this study, the investigators plan specifically

• To investigate the biodistribution and kinetics of the tracer 3-[11C]-OHB
• To estimate the radiation exposure of 3-[11C]-OHB by intravenous and oral administration of the tracer

Methods:

Six healthy and overweight (BMI: 28-40 kg/m^2) aged 50-70 years will undergo two PET/CT scans with 3-[11C]-OHB. One scan will be performed with the injection of 200 MBq of tracer and the other one will be performed with the subjects orally ingestion 100 MBq of the tracer. Following administration of the tracer, dynamic PET scans over the whole body will be performed to measure the biodistribution and radiation exposure of the tracer.

Inclusion criteria

• Age between 50-70 years
• BMI: 20-30 kg/m^2

Exclusion criteria

• All drugs that could affect the outcome
• HbA1c > 48 mmol/mol
• Known heart failure og episodes of acute myocardial infarction
• Liver disease ALAT > higher than 3 times of the normal level
• Kidney disease eGFR < 60 ml/min
• Blood donation in the last 3 months before inclusion
• Participation in other studies with radiation in the last 6 months
• Alcohol addiction