Early detection of the process of vascular calcification with novel bone seeking radiopharmaceuticals using SPECT-CT and P ET-CT

Student thesis: Doctoral ThesisDoctor of Philosophy


Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are clinically established sensitive molecular imaging modalities. However, their use in clinical cardiology remains limited. Early or intermediate stages of vascular calcification are thought to enhance plaque vulnerability. Computed tomography (CT), the “gold standard” for clinical imaging of calcification, fails to detect the early stages of calcification. PET and SPECT imaging may be used to detect the early stages of calcification in vivo.

The aim of the project was to evaluate novel and clinically established bone seeking SPECT and PET agents for imaging vascular calcification using experimental animal models. Technetium-99m labelled methylene diphosphonate (99mTc-MDP), fluorine-18 sodium fluoride (18F-NaF) and the novel bone seeking agents technetium-99m labelled dipicolylamine alendronate (99mTc-DPA Ale) and nitrido bis(dithiocarbamatebisphospho nate) (99mTc-N (DTCBP)2) were tested in vitro and for imaging in vivo using rat models of medial vascular calcification.

In the initial in vitro studies the bone seeking radiotracers described here demonstrated their potential for avid binding with different minerals, both of biological and synthetic origin, with 99mTc-DPA-Ale and 18F-NaF binding most efficient. Rat models for vascular calcification were established by diet modification and sub-cutaneous injections. For optimising the in vivo imaging protocol, a robust rat model with extensive calcification was established by feeding a special warfarin diet and sub-cutaneous administration of vitamin D3. Another model, with slow and progressive calcification, was achieved by feeding rats with warfarin diet only, and was found to be an ideal candidate for the longitudinal imaging study. In vivo imaging with animal models for vascular calcification revealed that the radiotracers can detect vascular calcification earlier than computed tomography. Longitudinal studies with the calcified rat model showed that the radiotracers can also play a role in monitoring disease progression.

However, the study also revealed several unexpected findings. SPECT and PET images showed radiotracer uptake in the abdominal aorta and mesenteric artery. Histological evidence of calcification was seen in the thoracic aorta which was not detected on SPECT and PET imaging. Histological sections also revealed that the calcified regions in the abdominal aorta are in proximity to the lumen whereas in the thoracic aorta they are deep seated, close to the adventitia which may account for the differential in uptake. The longitudinal imaging study showed that uptake of the radiotracers also reduced with maturity in calcification. These findings raise some intriguing questions, and answering them would help in a better understanding of the process of vascular calcification and developing strategies for in vivo imaging with SPECT-CT and PET-CT.

In conclusion, bone seeking radiopharmaceuticals have the potential to be used as agents for early diagnosis of vascular calcification and further study needs to be done to address the interesting questions raised in this thesis.
Date of Award2015
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorCathy Shanahan (Supervisor) & Philip Blower (Supervisor)

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