mechanisms of localization

biodistribution

body acting on radiopharmaceutical, may move and localize in organs, tissues, and compartments

then radioactivity does the work

what are the mechanisms of localization

active transport

simple diffusion/passive transport

ion exchange

physiochemical absorption

capillary blockade

phagocytosis

cell sequestration

compartmental localization

antigen-antibody complexation

receptor

chemotaxis

metabolism

active transport

cellular metabolic processes that result in organ or tissue concentrations above plasma levels, requires energy ("active" process)

Na+/K+ pump

active transporter that moves three Na+ out of a cell and two K+ into the cell against their respective concentration gradients

(not selective for K ions but for monovalent cations of certain ionic radius)

what are examples of active transport with radiodrugs

Tl201 and Rb82, iodine localization

potassium analogues

Thallium201, Rubidium82

how does uptake of Tl201 and Rb82 work?

uptake in cardiac cells directly proportional to perfusion and viability of the cells

positive (+) charge, hydrophilic (water-loving)

utilize Na+/K+ pump

what drug uses active transport for thyroid imaging

I123 sodium iodide

what is used for radioiodine therapy

liquid I131 in capsule

thyroid

signs and symptoms of hypothyroidism

tiredness, depression, goiter, puffy face, slow heartbeat, dry skin, cold intolerance, weight gain, dry skin, heavy periods, constipation

signs and symptoms of hyperthyroidism

nervousness, bulging eyes, goiter, rapid heartbeat, increased sweating, heat intolerance, weight loss, scant periods, frequent BM, warm palms, finger tremors

synthesis of thyroid hormone

1. trapping of iodine

2. oxidation of iodine

3.organification

4.condensation or coupling

5.release of T3 and T4

organification

binding of iodine with thyroglobulin molecule

what is used to trap iodide

iodide pump

what hormones require iodine for production

T3 (triiodothyronine) and T4 (thyroxine)

TRH

thyrotropin releasing hormone

TSH

thyroid stimulating hormone

thyroid hormone regulation loop

1. hypothalamus releases TRH to pituitary gland

2. pituitary gland releases TSH to thyroid

3. thyroid gland releases thyroid hormone

4.circulating free T3 and T4

(T3 and T4 set off negative feedback loop)

T3 and T4 negative feedback loop

T3/T4 goes to hypothalamus & anterior pituitary gland and tells them to either secrete more or less TRH/TSH

iodine

I-

iodide

I2

difference between iodide and iodine

iodide is used in body for thyroid (bioavailable) , iodine is elemental form

I- shape

spherical shape

TcO4- shape

tetrahedral

what most closely resembles I in its biologic behavior

Tc99mO4- (pertechnetate)

where does pertechnetate localize

in thyroid, salivary glands, gastric mucosa and choroid plexus of brain

how does pertechnetate localize

like iodine but will not get trapped and turn into thyroid hormone

I123 is better for imaging overall, specifically functional imaging than sodium pertechnetate.

true

secretion (technically active transport)

transport out of glands or tissues

what is similar between sodium pertechnetate and iodine

size, allows both to be used for thyroid imaging

what drug uses tubular secretion for kidney imaging

Tc99m MAG-3 (mertiatide)

simple diffusion/passive transport

movement of substance from regions of higher concentration to lower concentration

perfusion

random movement of molecules with net effect of uniform concentration

radiopharmaceutical localization with perfusion

-many times coupled with retention mechanism

-passive diffusion gets radiodrug to areas of interest, something else causes it to stick

what imaging agents (4) use simple diffusion

brain imaging agents

cardiac imaging agents

kidney imaging agents

bone imaging agents

99mTc-DTPA uses simple diffusion in brain scans via

good cerebral blood flow, followed by clearing with no brain

99mTc-DTPA uses passive diffusion via kidney filtration driven by

pressure (hydrostatic or osmotic)

18F-FDG uses facilitated diffusion via

like a revolving door with escort, glucose transporters

can be inhibited due to limited # of doors

carrier-mediated

ion exchange

the exchange of ions of the same charge between an insoluble solid and a solution in contact with it, occurs at active bone growth/repair sites due to increased turnover of calcium and hydroxyl ions

what can be substituted for calcium ions

89Sr (Metastron)

223Ra (Xofigo)

what can be substituted for hydroxyl ions

18F (fluoride)

chemisorption

the binding of a species to a surface by chemical bonding forces, covalent and hydrogen bonding

what radiodrugs use chemisorption

99mTc labeled phosphate complexes

i.e. 99mTc-MDP, 99mTc-HDP, 153m Lexidronam)

absorption onto surface of hydroxyapatite crystals

what scan uses chemisorption

whole body bone scans

capillary blockade

upon IV injection, particles larger than RBC will become lodged in first capillary bed they encounter

99mTc MAA (macroaggregated albuminum)

uses capillary blockades for lung imaging

particle limit of MAA

200-800k particles per dose

what can be used to determine dimension of not less than 100 MAA particles

hemacytometer grid by optical microscopy

true

more than 90% (at least) MAA particles have 10-90um diameter range (Pulmotech)

true

90% within 10-70 um diameters for generic

no particle exceeds 150um

true.

ideal # of MAA particles in normal adult dose

350,000

what occurs if too few MAA particles are injected

statistical parameters may lead to false-positive results

what occurs if too many MAA particles are injected

unnecessary occlude pulmonary capillaries

phagocytosis

process by which phagocytes remove foreign particulate matter from blood circulation

engulf and ingest foreign particles

recognition and removal of small foreign particles in blood by the cells of reitculoendothelial (RE) system

biodistribution of RE cells

85% in liver

10% in spleen

5% in bone marrow

if shunt is suspected in heart, how many MAA particles should be used

50,000 or less

what uses phagocytosis to create scintillation image of liver

99mTc sulfur colloid

average size of 99mTc sulfur colloid

0.1 um

cell sequestration

process by which spleen recognizes and removes damaged red blood cells or cells near end of life

what method is used when injecting 99mTc into damaged red blood cells

cell sequestration

compartmental localization

when radiopharmaceuticals are introduced directly into the well-defined body compartments and remain there long enough for imaging to be performed

ventilation scans with 133Xe

example of compartmental localization

gastric emptying study with 99mTc sulfur colloid

example of compartmental localization

CSF study with In-111 DTPA

example of compartmental localization

antigen-antibody complexation

using labeled antibodies for the immunodetection and immunotherapy of a variety of diseases (particular oncologic nature)

monoclonal antibodies

a collection of identical antibodies that interact with a single antigen site

antibody

protein that acts against a specific antigen

antigen

protein that, when introduced in the blood, triggers the production of an antibody

90Y-Ibritumomab Tiuxetan (Zevalin)

uses antigen-antibody complexation to treat non-Hodgkins lymphoma (NHL)

monoclonal antibodies

a collection of identical antibodies that interact with a single antigen site

drawbacks of radiolabeled MoAb

-significant cross-reactivity with other antigens

-poor target-to-nontarget in vivo

-human antimouse antibody (HAMA) immune responses

receptor binding

changes in receptor concentration are thought to be related to certain disease states

drug receptors

specific cellular site that interacts with drug molecule mediating action

located in/on cells or within cell itself

affected by micromolar to nanomolar concentrations

selectively blocked by drug antagonists

111In-pentetreotide (OctreoScan)

radiodrug binds to somatostatin receptors on cell surfaces throughout the body

(no longer used)

DTPA conjugate of octreotide

Octreoscan

kit for prep of 111In-pentetreotide

octreotide

long-acting analog of human hormone somatostatin

NETSPOT

kit for prep of 68Ga-dotatate

68Ga-dotatate

binds to somatostatin receptors with highest affinity for subtype 2 receptors

indicated for use with PET for localization

what is 68Ga-dotatate used for

localization of somatostatin receptor positive neuroendocrine tumors (NETS) in peds and adults

Lutathera

177Lu Dotatate

What is 177Lu-dotatate used for?

neuroendocrine tumors treatment

theranostics

involves combining diagnostic imaging and therapy with same molecule which is radiolabeled differently or administered in other dosages

chemotaxis

movement of cell in response to chemical stimulus

when would imaging utilize radiolabeled white blood cells

infection

what are 3 molecules that are naturally occurring that are metabolic analogues

13N ammonia

11C flucose, fatty acid

15O water

foreign label incorporated metabloic analogues

18F-FDG (uses facilitated diffusion)

what is 18F-FDG used for

cancer imaging (mets, diagnosis)

brain imaging