This document discusses various techniques for functional, physiological, and molecular imaging. It provides examples of molecular imaging targeting specific biomarkers like VEGF, sodium iodide symporter, and somatostatin receptors. It also summarizes the imaging reporter gene concept and provides examples of imaging hypoxia inducible factor 1 and p53 expression in experimental animals. Combined physiological and molecular imaging of lung cancer utilizing FDG-PET, CT, and DCE-CT is shown. Models for contrast agent exchange and Patlak graphical analysis are presented.

1. 7
Functional, Physiological and
Molecular Imaging
DR MUHAMMAD BIN ZULFIQAR
PGR III FCPS Services institute of Medical
Sciences/ Services Hospital Lahore
GRAINGER & ALLISON’S DIAGNOSTIC RADIOLOGY

2. • FIGURE 7-1 ■ A plot of echogenicity against
triggering interval for microbubble infusion
will be asymptotic. The initial upslope (thick)
measures microcirculatory flow speed whilst
the asymptote measure is proportional to
fractional vascular volume. (After Wei K et
al.12)

3. • FIGURE 7-2 ■ Examples of ‘everyday’ molecular imaging. (A) Peak contrast enhancement of a lung
nodule (arrow) on C correlates with expression of vascular endothelial growth factor (VEGF). (B)
Uptake of radioiodine (131I) in miliary lung metastases (arrowheads) of thyroid cancer reflecting
expression of the sodium/iodide (Na+/I–) symporter. (C) Uptake of 111In-octreotide in a pelvic
carcinoid tumour (arrow) indicates expression of somatostatin receptors. (D) Uptake of 18F-
fluorodeoxyglucose (FDG) in multiple metastases due to expression of Glut-1 glucose transporters.

4. • FIGURE 7-2 ■ Examples
of ‘everyday’ molecular
imaging. (A) Peak
contrast enhancement
of a lung nodule (arrow)
on C correlates with
expression of vascular
endothelial growth
factor (VEGF). (B) Uptake
of radioiodine (131I) in
miliary lung metastases
(arrowheads) of thyroid
cancer reflecting
expression of the
sodium/iodide (Na+/I–)
symporter. (C) Uptake of
111In-octreotide in a
pelvic carcinoid tumour
(arrow) indicates
expression of
somatostatin receptors.
(D) Uptake of 18F-
fluorodeoxyglucose
(FDG) in multiple
metastases due to
expression of Glut-1
glucose transporters.

5. • FIGURE 7-3 ■ Summary of the imaging reporter gene concept. The
reporter gene is incorporated into the nuclear DNA of the target
cells by transfection (e.g. viral vector). If the reference gene is
active, the cell translates the reporter gene to produce reporter
messenger RNA (mRNA) which is translated to the reporter protein.
The reporter substrate interacts with the reporter protein to
produce an imaging signal (e.g. gamma ray, paramagnetic effect).

6. • FIGURE 7-4 ■ Molecular imaging and hypoxia
inducible factor1 (HIF1). HIF-1 activity is increased by
tissue hypoxia and oncogene mutations. Increased HIF-
1 activity upregulates several molecules with biological
effects that are accessible to non-invasive imaging. FDG
= fluorodeoxyglucose, MDR = multidrug resistance,
MIBI = methoxyisobutylisonitrile, pgp = p-glycoprotein,
VEGF = vascular endothelial growth factor.

7. • FIGURE 7-5 ■ Functional CT images of cerebral
blood volume (CBV: left) and cerebral blood flow
(CBF: right) in acute stroke. The infarct core (red
outline) shows matched reductions in CBV and
CBF. The surrounding penumbra (white outline)
demonstrates preserved CBV despite reduced
CBF reflecting upregulation of nitric oxide (NO)
secondary to increased activity of HIF-1. (Adapted
from Miles and Griffiths.49)

8. • FIGURE 7-6 ■ Indirect molecular imaging of the expression of p53 (A) and HIF1 (B) in experimental
animals. (A) Positive and negative control tumours were grafted onto the left shoulder and left
thigh, respectively. The test tumour on the right shoulder only accumulates radioactivity after
activation of the p53 pathway in response to DNA damage produced by administration ofN,N′-
bis(2- chloroethyl)-N-nitrosourea (BCNU). (From Doubrovin M, Pnonmarev V, Beresten T et al 2001
Imaging transcriptional regulation of p53- dependent genes with positron emission tomography in
vivo. Proc Natl Acad Sci 98: 9300–9305.) (B) Tumours grafted onto the animal’s left side accumulate
radioactivity due to activation of HIF-1. Greater activity is seen in larger tumours, reflecting more
severe hypoxia. Control tumours on the animal’s right side show no accumulation of radioactivity.
(From Serganova I, Doubrovin M, Vider J et al 2004 Molecular imaging of temporal dynamics and
spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living
mice. Cancer Res 64: 6101–6108. With permission of the American Association for Cancer
Research.)

9. • FIGURE 7-6 ■ Indirect molecular imaging of the expression of p53 (A) and HIF1 (B)
in experimental animals. (A) Positive and negative control tumours were grafted
onto the left shoulder and left thigh, respectively. The test tumour on the right
shoulder only accumulates radioactivity after activation of the p53 pathway in
response to DNA damage produced by administration of N,N′-bis(2- chloroethyl)-
N-nitrosourea (BCNU). (From Doubrovin M, Pnonmarev V, Beresten T et al 2001
Imaging transcriptional regulation of p53- dependent genes with positron
emission tomography in vivo. Proc Natl Acad Sci 98: 9300–9305.) (B) Tumours
grafted onto the animal’s left side accumulate radioactivity due to activation of
HIF-1. Greater activity is seen in larger tumours, reflecting more severe hypoxia.
Control tumours on the animal’s right side show no accumulation of radioactivity.
(From Serganova I, Doubrovin M, Vider J et al 2004 Molecular imaging of temporal
dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal
transduction activity in tumors in living mice. Cancer Res 64: 6101–6108. With
permission of the American Association for Cancer Research.)

10. • FIGURE 7-7 ■
Combined
physiological and
molecular imaging of
leftsided nonsmall cell
lung cancer. (A)
Conventional CT. (B)
Molecular imaging of
tumour glucose
metabolism with FDG-
PET. (C) Physiological
imaging of tumour
blood flow with DCE-CT.

11. • FIGURE 7-8 ■ The simplest
twocompartmental model in which exchange
occurs from plasma to interstitium governed
by a rate constant k1.

12. • FIGURE 7-9 ■ Patlak graphical analysis. If a(t)
is vascular concentration and c(t) is tissue
concentration, a plot of c(t)/a(t) against
.a(t)dt/a(t) will tend towards a straight line.