26.1 Radioisotopes, Radiopharmaceuticals & Gamma Camera / SPECT Operation

26.1 Radioisotopes, Radiopharmaceuticals & Gamma Camera / SPECT Operation

Introduction to Nuclear Medicine Principles

Unlike structural diagnostic imaging modalities (such as conventional projection radiography and computed tomography) which measure differential X-ray beam attenuation through anatomical structures, Nuclear Medicine is a functional imaging modality. Radiopharmaceuticals—chemical compounds tagged with radioactive isotopes—are introduced into the human body (via intravenous injection, oral ingestion, or inhalation) to evaluate physiology, metabolism, organ perfusion, and cellular biochemistry.

The radiologic technologist (RadTech) specializing in nuclear medicine must master the physical principles of radioactive decay, radionuclide generator operation, radiopharmaceutical synthesis, gamma camera instrumentation, and cross-sectional SPECT/CT reconstruction.

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Radioisotopes & Radioactive Decay Modes

Radionuclides are unstable atomic nuclei containing an excess of mass or energy that undergo spontaneous transformation (radioactive decay) to attain nuclear stability, emitting particulate or electromagnetic radiation in the process.

+-------------------------------------------------------------------------+
|                        RADIOACTIVE DECAY MODES                          |
+-------------------+-------------------+-------------------+-------------+
|    ALPHA (a)      |   BETA MINUS (b-) |  BETA PLUS (b+)   |  GAMMA (g)  |
|  - He-4 nucleus   |  - Neutron -> p+  |  - Proton -> n    |  - Isomeric |
|  - High LET       |  - Emits e- + v_  |  - Emits e+ + v   |    Transition|
|  - Non-penetrate  |  - Therapy use    |  - PET imaging    |  - Pure photon|
|  - High hazard    |  - e.g., I-131    |  - e.g., F-18     |  - Tc-99m   |
+-------------------+-------------------+-------------------+-------------+

1. Primary Modes of Nuclear Decay

• Alpha Decay ($\alpha$): Emission of a helium nucleus ($^4_2\text{He}$, comprising 2 protons and 2 neutrons). Alpha particles possess high Linear Energy Transfer (LET) and high mass, penetrating only a few micrometers in soft tissue ($<100 \ \mu\text{m}$). Alpha emitters (e.g., Radium-223) cause severe localized double-strand DNA damage and are restricted strictly to targeted radionuclide therapy, never diagnostic imaging.
• Beta-Minus Decay ($\beta^-$): Occurs in neutron-rich nuclei. A neutron transforms into a proton, emitting a high-speed electron (negatron, $\text{e}^-$) and an antineutrino ($\bar{\nu}$): $\text{n} \rightarrow \text{p}^+ + \text{e}^- + \bar{\nu}$ Beta-minus particles penetrate several millimeters into tissue. While $\beta^-$ emitters are widely used in therapy (e.g., Iodine-131 for thyroid ablation, Strontium-89 for bone pain palliation), their continuous bremsstrahlung and tissue ionizations create unnecessary patient radiation dose, making pure $\beta^-$ emitters unsuitable for diagnostic gamma camera imaging.
• Beta-Plus Decay ($\beta^+$ / Positron Emission): Occurs in proton-rich nuclei. A proton transforms into a neutron, emitting a positron (anti-electron, $\text{e}^+$) and a neutrino ($\nu$): $\text{p}^+ \rightarrow \text{n} + \text{e}^+ + \nu$ The emitted positron travels a short distance ($0.5 \text{ to } 2.0 \text{ mm}$) before annihilating with an electron, producing two $511 \ \text{keV}$ gamma photons used in PET imaging.
• Gamma Decay ($\gamma$) & Isomeric Transition (IT): Following particle emission, a daughter nucleus often remains in an excited nuclear energy state (metastable state, designated by 'm'). The nucleus transitions to its ground state by emitting pure electromagnetic energy in the form of a gamma photon ($\gamma$) without changing its atomic number ($Z$) or mass number ($A$): $^{99m}_{43}\text{Tc} \rightarrow ^{99}_{43}\text{Tc} + \gamma \ (140 \ \text{keV})$ Isomeric transition is the ideal decay mode for diagnostic imaging because gamma photons readily exit the body to reach external detectors without causing high local tissue ionization.
• Electron Capture (EC): A proton-rich nucleus captures an inner-shell electron (usually K-shell), transforming a proton into a neutron ($p^+ + e^- \rightarrow n + \nu$). The resulting orbital vacancy is filled by an outer-shell electron, emitting characteristic X-rays or Auger electrons (e.g., Iodine-123, Thallium-201, Gallium-67).

2. Radioactive Decay Kinetics & Half-Life Equations

The rate of decay of a radioactive sample is its Activity ($A$), measured in Becquerels ($1 \ \text{Bq} = 1 \ \text{disintegration/second}$) or Curies ($1 \ \text{Ci} = 3.7 \times 10^{10} \ \text{Bq} = 37 \ \text{GBq}$).

• Physical Half-Life ($T_{1/2}$ or $T_p$): The time required for a radioactive sample to decay to exactly $50%$ of its initial activity: $A(t) = A_0 e^{-\lambda t} = A_0 \left(\frac{1}{2}\right)^{\frac{t}{T_{1/2}}}$
• Decay Constant ($\lambda$): The fractional rate of decay per unit time: $\lambda = \frac{\ln(2)}{T_{1/2}} = \frac{0.693}{T_{1/2}}$
• Biological Half-Life ($T_b$): The time required for the biological organism to eliminate $50%$ of an administered substance via metabolic excretion (urine, feces, sweat).
• Effective Half-Life ($T_e$): The actual time required for the internal radioactivity in a patient to drop by $50%$, combining physical decay and biological clearance: $\frac{1}{T_e} = \frac{1}{T_p} + \frac{1}{T_b} \implies T_e = \frac{T_p \times T_b}{T_p + T_b}$ Note: The effective half-life ($T_e$) is always shorter than either the physical half-life ($T_p$) or biological half-life ($T_b$) alone.

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Technetium-99m Properties & The Mo-99 Generator

1. Physical Properties of Technetium-99m ($^{99m}\text{Tc}$)

Technetium-99m is the workhorse of modern diagnostic nuclear medicine, accounting for over $85%$ of all clinical diagnostic studies worldwide. Its dominance is due to ideal physical characteristics:

1. Ideal Gamma Energy ($140 \ \text{keV}$): High enough to readily penetrate soft tissue and exit the patient's body, but low enough to be efficiently stopped and absorbed by relatively thin ($3/8 \ \text{inch}$) Sodium Iodide $\text{NaI(Tl)}$ scintillation crystals with high spatial resolution.
2. Pure Gamma Emitter: Decays via isomeric transition ($98.6%$) without emitting damaging alpha or beta particles, keeping patient absorbed dose minimal.
3. Optimal Physical Half-Life ($6.01 \ \text{hours}$): Long enough to complete complex multi-hour radiopharmaceutical preparation and patient imaging procedures, but short enough to decay rapidly, minimizing patient radiation exposure.
4. Versatile Synthetic Chemistry: As a transition metal ($Z=43$), technetium can exist in oxidation states from $-1$ to $+7$, allowing it to bind to a wide variety of chemical chelates to target specific organs.

2. Molybdenum-99 / Technetium-99m Generator ("Moly Cow")

Because $^{99m}\text{Tc}$ has a short half-life of 6 hours, storing pre-made inventory is impractical. Instead, hospitals utilize a radionuclide generator system on site.

+-------------------------------------------------------------------------+
|                 Mo-99 / Tc-99m GENERATOR ("MOLY COW")                   |
+-------------------------------------------------------------------------+
|  [ Sterile Saline Vial (0.9% NaCl) ] -> Eluent Inlet                    |
|                                                                         |
|           +-----------------------------------------+                   |
|           |   Lead / Depleted Uranium Shielding     |                   |
|           |                                         |                   |
|           |     +-----------------------------+     |                   |
|           |     | Alumina Column (Al2O3)      |     |                   |
|           |     | Mo-99 adsorbed as MoO4(2-)  |     |                   |
|           |     +-----------------------------+     |                   |
|           |                    |                    |                   |
|           |        Mo-99 (T1/2 = 66 h)              |                   |
|           |          | (Beta decay 87%)             |                   |
|           |          v                              |                   |
|           |        Tc-99m (T1/2 = 6.01 h)           |                   |
|           |        (Forms TcO4- pertechnetate)      |                   |
|           +-----------------------------------------+                   |
|                                |                                        |
|                                v                                        |
|  [ Evacuated Collection Vial ] -> Eluates Sodium Pertechnetate (NaTcO4) |
+-------------------------------------------------------------------------+

• Parent & Daughter Kinetics: Parent radionuclide Molybdenum-99 ($^{99}\text{Mo}$, $T_{1/2} = 66 \ \text{hours}$) is produced in a nuclear reactor by fission of Uranium-235 ($^{235}\text{U}$). $^{99}\text{Mo}$ decays via $\beta^-$ emission ($87%$) into daughter Technetium-99m ($^{99m}\text{Tc}$, $T_{1/2} = 6.01 \ \text{hours}$).
• Transient Equilibrium: Because the parent half-life ($66 \ \text{h}$) is approximately $11$ times longer than the daughter half-life ($6.01 \ \text{h}$), the system achieves transient equilibrium after approximately 4 half-lives ($\sim 23 \ \text{hours}$). At transient equilibrium, daughter activity reaches its peak and appears to decay with the physical half-life of the parent ($66 \ \text{h}$). Generators are typically eluted ("milked") daily at 24-hour intervals.
• Column Mechanism: Anized Alumina ($\text{Al}_2\text{O}_3$, aluminum oxide) is packed inside a sterile glass column. Acidified molybdate ions ($^{99}\text{MoO}_4^{2-}$) bind tightly to the alumina column. As $^{99}\text{Mo}$ decays into $^{99m}\text{Tc}$, pertechnetate ions ($^{99m}\text{TcO}_4^-$) are formed. Pertechnetate has a single negative charge and exhibits very low affinity for alumina.
• Elution Process: Passing sterile $0.9%$ Normal Saline ($\text{NaCl}$) through the column washes off the loose $^{99m}\text{TcO}_4^-$, yielding Sodium Pertechnetate ($\text{Na}^{99m}\text{TcO}_4$) in the eluate, while $^{99}\text{Mo}$ remains tightly bound to the column.

3. Generator Quality Control (Mandatory Purity Tests)

Before administering generator eluate to patients, three mandatory quality control tests must be performed:

1. Radionuclidic Purity ($\text{Mo-99}$ Breakthrough):
   • Definition: Measures the fraction of total radioactivity present as the parent radionuclide $^{99}\text{Mo}$ relative to $^{99m}\text{Tc}$. Excess $^{99}\text{Mo}$ increases patient radiation dose significantly due to its high-energy beta emissions.
   • Test Method: The eluate vial is placed inside a heavy lead shield (lead pig) in a dose calibrator. The lead shield absorbs all $140 \ \text{keV}$ gamma rays from $^{99m}\text{Tc}$, but allows high-energy $740 \ \text{keV}$ and $780 \ \text{keV}$ gamma rays from $^{99}\text{Mo}$ to penetrate and be measured.
   • USP / NRC Limit: Less than $0.15 \ \mu\text{Ci}$ of $^{99}\text{Mo}$ per $1 \ \text{mCi}$ of $^{99m}\text{Tc}$ (or $<0.15 \ \text{kBq } ^{99}\text{Mo} / \text{MBq } ^{99m}\text{Tc}$) at the time of patient administration.
2. Chemical Purity (Alumina Breakthrough):
   • Definition: Measures the concentration of dissolved aluminum ions ($\text{Al}^{3+}$) washed off the column into the eluate. Excess $\text{Al}^{3+}$ causes chemical precipitation of radiopharmaceuticals (e.g., causing aggregation of $^{99m}\text{Tc-MDP}$ in the liver instead of bone).
   • Test Method: Colorimetric spot test using aluminon indicator paper compared against a $10 \ \mu\text{g/mL}$ aluminum standard solution.
   • USP Limit: Less than $10 \ \mu\text{g}$ of $\text{Al}^{3+}$ per $1 \ \text{mL}$ of eluate in fission-produced generators.
3. Radiochemical Purity:
   • Definition: Measures the percentage of total $^{99m}\text{Tc}$ activity bound in the desired chemical form (e.g., bound $^{99m}\text{Tc-MDP}$) versus unbound free pertechnetate ($\text{TcO}_4^-$) or hydrolyzed-reduced technetium ($\text{TcO}_2$). Unbound free pertechnetate causes non-diagnostic uptake in the stomach, thyroid gland, and salivary glands.
   • Test Method: Instant Thin-Layer Chromatography (ITLC).
   • USP Limit: Greater than $90% \text{ to } 95%$ bound radiopharmaceutical purity (depending on specific product specification).

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Radiopharmaceuticals & Clinical Applications

Radiopharmaceuticals consist of two parts: a radionuclide (tag/marker emitting radiation) and a pharmaceutical vehicle (chemical complex determining biological biodistribution).

1. Key Technetium-99m Radiopharmaceuticals

• $^{99m}\text{Tc-MDP}$ (Methylene Diphosphonate): Bone scintigraphy. Chemisorbs directly onto the hydroxyapatite crystal surface in areas of active osteogenesis and bone remodeling (detects metastases, fractures, osteomyelitis).
• $^{99m}\text{Tc-Sestamibi}$ (Cardiolite) / $^{99m}\text{Tc-Tetrofosmin}$: Myocardial perfusion imaging (MPI) and parathyroid adenoma localization. Lipophilic cations that cross cell membranes and accumulate proportionally to blood flow within myocardial cell mitochondria.
• $^{99m}\text{Tc-HMPAO}$ (Exametazime) & $^{99m}\text{Tc-ECD}$ (Bicisate): Regional cerebral blood flow (rCBF) brain perfusion imaging. Neutral lipophilic complexes that cross the blood-brain barrier and convert into hydrophilic metabolites trapped inside brain parenchyma. $^{99m}\text{Tc-HMPAO}$ is also used to label autologous leukocytes (white blood cells) for infection and occult abscess localization.
• $^{99m}\text{Tc-MAA}$ (Macroaggregated Albumin): Lung perfusion imaging. Particles ($10 \text{ to } 90 \ \mu\text{m}$) cause temporary precapillary microembolization in pulmonary capillary beds proportional to pulmonary blood flow.
• $^{99m}\text{Tc-DTPA}$ (Diethylenetriaminepentaacetic acid): Renal glomerular filtration rate (GFR) measurement and aerosol lung ventilation imaging.
• $^{99m}\text{Tc-MAG3}$ (Mercaptoacetyltriglycine): Renal tubular secretion / effective renal plasma flow (ERPF) evaluation.
• $^{99m}\text{Tc-Sulfur Colloid}$: Reticuloendothelial system (RES) imaging (liver/spleen phagocytosis by Kupffer cells), lymphoscintigraphy (sentinel node mapping), and gastrointestinal transit/bleeding studies.

2. Non-Technetium Radiopharmaceuticals

• Iodine-131 ($^{131}\text{I}$): $T_{1/2} = 8.02 \ \text{days}$. Emits high-energy $\beta^-$ ($606 \ \text{keV}$) and primary $\gamma$ ($364 \ \text{keV}$). Used for thyroid carcinoma therapy, remnant ablation, and Graves' disease hyperthyroidism treatment (beta particles destroy thyroid tissue).
• Iodine-123 ($^{123}\text{I}$): $T_{1/2} = 13.2 \ \text{hours}$, EC decay, pure $\gamma$ ($159 \ \text{keV}$). Ideal diagnostic imaging agent for thyroid uptake scans and MIBG imaging (pheochromocytoma/neuroblastoma).
• Thallium-201 ($^{201}\text{Tl}$): $T_{1/2} = 73 \ \text{hours}$, EC decay. Emits low-energy characteristic Mercury X-rays ($68 \text{ to } 80 \ \text{keV}$) and gammas ($135, 167 \ \text{keV}$). Potassium analog taken up by $\text{Na}^+/\text{K}^+$ ATPase pump; historically used for myocardial viability.
• Gallium-67 ($^{67}\text{Ga}$): $T_{1/2} = 78 \ \text{hours}$, EC decay, multiple photopeaks ($93, 185, 300, 394 \ \text{keV}$). Binds bacterial siderophores and transferrin; used for chronic inflammation, fever of unknown origin (FUO), and lymphoma evaluation.
• Indium-111 ($^{111}\text{In}$): $T_{1/2} = 2.8 \ \text{days}$, EC decay, photopeaks at $171 \ \text{keV}$ and $245 \ \text{keV}$. Used for $^{111}\text{In}$-DTPA cisternography and autologous leukocyte ($^{111}\text{In}$-oxine WBC) infection imaging.

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Diagnostic Radioisotopes Summary

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Instrumentation: Anger Gamma Camera Architecture

The Anger Gamma Camera (invented by Hal Anger in 1957) is the primary stationary imaging device in nuclear medicine. It detects gamma photons emitted from the patient and reconstructs their spatial position and energy.

+-------------------------------------------------------------------------+
|                    ANGER GAMMA CAMERA ARCHITECTURE                      |
+-------------------------------------------------------------------------+
|                           [ PATIENT ORGAN ]                             |
|                                   |                                     |
|                           Gamma Photons (140 keV)                       |
|                                   v                                     |
|  +-------------------------------------------------------------------+  |
|  | LEAD COLLIMATOR (Parallel Hole, Pinhole, etc.)                   |  |
|  +-------------------------------------------------------------------+  |
|                                   | (Rejects oblique scatter)           |
|                                   v                                     |
|  +-------------------------------------------------------------------+  |
|  | NaI(Tl) SCINTILLATION CRYSTAL (3/8" Thick, Emits 415 nm Light)    |  |
|  +-------------------------------------------------------------------+  |
|                                   | (Visible Light Photons)             |
|                                   v                                     |
|  +-------------------------------------------------------------------+  |
|  | LIGHT GUIDE / OPTICAL COUPLING                                    |  |
|  +-------------------------------------------------------------------+  |
|                                   |                                     |
|  +-------------------------------------------------------------------+  |
|  | PHOTOMULTIPLIER TUBES (PMT Array) - Photocathode -> Dynodes       |  |
|  +-------------------------------------------------------------------+  |
|                                   | Electrical Pulses                   |
|                                   v                                     |
|  +-------------------------------------------------------------------+  |
|  | PREAMPLIFIERS & ANGER POSITIONING LOGIC (X+, X-, Y+, Y-)          |  |
|  +-------------------------------------------------------------------+  |
|                                   | Z = Total Energy Pulse              |
|                                   v                                     |
|  +-------------------------------------------------------------------+  |
|  | PULSE HEIGHT ANALYZER (PHA Window: 140 keV ± 10% / 126-154 keV)   |  |
|  +-------------------------------------------------------------------+  |
|                                   | Validated Photopeak Events          |
|                                   v                                     |
|                         [ DIGITAL IMAGE DISPLAY ]                       |
+-------------------------------------------------------------------------+

1. Lead Collimator

• Function: Placed on the front face of the detector. Because gamma rays cannot be focused by optical lenses, collimators use thick lead or tungsten channels (septa) to absorb scattered or oblique gamma rays, permitting only photons traveling parallel to the hole axes to reach the crystal. The collimator defines the spatial origin of detected photons.
• Collimator Types:
  • Parallel-Hole: Standard collimator for routine imaging. Holes are parallel to each other. Image size equals actual organ size ($1:1$ ratio).
  • Pinhole: Single small aperture on a cone-shaped lead body. Produces an inverted, magnified image of small organs (e.g., thyroid gland, pediatric hip joints). Resolution increases as object-to-pinhole distance decreases.
  • Converging: Holes slant inward toward the patient. Magnifies smaller organs to fill the crystal surface.
  • Diverging: Holes slant outward away from the patient. Demagnifies large organs (e.g., full lung field) to fit a small crystal.
• Tradeoff: Spatial resolution is inversely proportional to sensitivity. High-Resolution (LEHR) collimators have longer, narrower holes (high resolution, lower count rate sensitivity), while High-Sensitivity collimators have shorter, wider holes.

2. Sodium Iodide Thallium-Doped $\text{NaI(Tl)}$ Scintillation Crystal

• Scintillation Mechanism: Converts absorbed high-energy gamma photons into thousands of low-energy visible light photons (scintillations at $\sim 415 \ \text{nm}$, blue light). The total light output is strictly proportional to the energy deposited by the absorbed gamma ray.
• Thallium Doping ($0.1%$): Pure NaI is an inefficient scintillator at room temperature; thallium (Tl) creates activator color centers within the crystal lattice that dramatically increase scintillation light conversion efficiency.
• Hygroscopic Nature: NaI(Tl) crystals absorb moisture from ambient air, causing yellow discoloration and clouding (ruining light transmission). Crystals must be hermetically sealed inside an airtight aluminum casing with a glass optical backplate window.
• Crystal Thickness: Standard thickness is $3/8 \ \text{inch}$ ($9.5 \ \text{mm}$).
  • Thinner crystal ($1/4 \ \text{inch}$): Higher spatial resolution, but lower detection sensitivity for $140 \ \text{keV}$ gammas.
  • Thicker crystal ($5/8 \ \text{inch}$): Higher detection sensitivity for high-energy gammas (e.g., $364 \ \text{keV}$ of $^{131}\text{I}$), but lower spatial resolution due to increased light spreading.

3. Light Guide & Photomultiplier Tube (PMT) Array

• An array of $37 \text{ to } 91$ hexagonal or square PMTs is optically coupled to the rear glass window of the crystal via clear optical grease or light guides.
• PMT Function: Converts visible scintillation light photons into an electrical current. Light strikes the photocathode to emit photoelectrons (photoelectric effect), which are accelerated through a series of $10 \text{ to } 14$ dynodes, multiplying the electron signal by $10^6 \text{ to } 10^8$ (high current gain).

4. Anger Positioning Logic & Pulse Height Analyzer (PHA)

• Spatial Positioning Logic: Signal amplitudes from surrounding PMTs are combined in an Anger resistor network to calculate spatial coordinates ($X^+, X^-, Y^+, Y^-$) of the scintillation event on the crystal face: $X = \frac{X^+ - X^-}{X^+ + X^-}, \quad Y = \frac{Y^+ - Y^-}{Y^+ + Y^-}$
• Total Energy Signal ($Z$): Summing signals from all PMTs yields total pulse height $Z$, which represents the total energy deposited in the crystal ($Z = X^+ + X^- + Y^+ + Y^-$).
• Pulse Height Analyzer (PHA): Filters incoming pulses by energy. Compton-scattered gamma photons lose energy inside the patient body and emerge with lower energies ($<140 \ \text{keV}$). If scattered photons were imaged, they would degrade image contrast and spatial resolution. The PHA establishes an energy window centered on the photopeak:
  • For $^{99m}\text{Tc}$ ($140 \ \text{keV}$), a standard $20%$ energy window ($140 \ \text{keV} \pm 10%$) accepts only energy pulses between $126 \ \text{keV}$ and $154 \ \text{keV}$, rejecting lower-energy Compton scatter.

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SPECT & SPECT/CT Hybrid Imaging

1. Single Photon Emission Computed Tomography (SPECT)

Conventional 2D planar scintigraphy suffers from overlapping tissue structures. SPECT utilizes one, two, or three gamma camera heads mounted on a rotating gantry that orbit $360^\circ$ around the patient (or $180^\circ$ for cardiac imaging), acquiring multiple 2D projection angles (typically $64 \text{ to } 128$ projections over $360^\circ$).

• Tomographic Reconstruction: Projection data are processed using Filtered Backprojection (FBP) or Ordered Subsets Expectation Maximization (OSEM) iterative reconstruction algorithms to generate 3D volumetric datasets displayed as cross-sectional axial, coronal, and sagittal slices.

2. Hybrid SPECT/CT Imaging

Hybrid SPECT/CT systems integrate a dual-head SPECT gamma camera and a multi-slice CT scanner mounted in tandem on a single gantry with a shared patient couch.

• Dual Advantages:
  1. Anatomical Coregistration: Overlays low-resolution functional SPECT molecular/metabolic data precisely onto high-resolution CT anatomical cross-sections (fused images), allowing exact localization of lesions (e.g., distinguishing bone metastases from degenerative joint disease).
  2. CT-Based Attenuation Correction (CT-AC): Deep tissue organs attenuate emitted gamma photons. SPECT/CT uses CT Hounsfield unit attenuation maps converted to $140 \ \text{keV}$ linear attenuation coefficients ($\mu$) to correct for photon absorption across varying tissue densities (lung, muscle, bone), producing accurate quantitative image reconstruction.