Purpose:It is often assumed that animal biodistributions of novel proteins are not dependent upon the radiolabel used in their determination. In units of percent injected dose per gram of tissue (%ID/g), organ uptake results (u) may be obtained using either iodine or metal as radioactive labels. Iodination is preferred as it is a one‐step process whereas metal labeling requires two chemical procedures and therefore more protein material. It is important to test whether the radioactive tag leads to variation in the uptake value.Methods:Uptakes of 3antibodies to Carcinoembryonic Antigen (CEA) were evaluated in a nude mouse model bearing 150 to 300 mg LS174T human colon cancer xenografts. Antibodies included diabody (56 kDa), minibody (80kDa) and intact M5A (150 kDa) anti‐CEA cognates. Both radioiodine and indium‐111 labels were used with uptakes evaluated at 7 time(t) points out to 96 h. Ratios (R) of u(iodine‐label)/u(indium‐label) were determined for liver, spleen, kidneys, lung and tumor.Results:Hepatic loss was rapid for diabody and minibody; by 24 h their R values were only 2%; i.e., uptake of iodine was 2% of that of indium for these 2 antibodies. By contrast, R for the intact cognate was 50% at that time point. Splenic results were similar. Tumor uptake ratios did not depend upon the antibody type and were 50% at 24 h.Conclusions:Relatively rapid loss of iodine relative to indium in liver and spleen was observed in lower mass antibodies. Tumor ratios were larger and independent of antibody type. Aside from tumor, the R ratio of uptakes depended on the antibody type. R values decreased monotonically with time in all tissues and for all cognates. Using this ratio, one can possibly correct iodine‐based u (t) results so that they resemble radiometal‐derived biodistributions.

Radiolabeled agents are being developed for TRT (Targeted Radionuclide Therapy). Included in the 50 to 200 nm scale of this project are liposomes, short segments of DNA or RNA, nanoparticles and proteins. Because of possibly multiple lesion sites, these radiopharmaceuticals (RPs) are usually given by IV injection. Targeting, which requires a number of hours to days to accomplish, is effected by various means. The simplest method is to have the agent pass out of the blood and into the tumor space using the fenestrations in tumor capillaries. Liposomes are one such example whose membranes are dissolved in the lesion so as to release vesicle contents. Among the most specific localization processes is protein binding to a molecular marker on ‐ or near ‐ the tumor cell. Among such markers are Carcinoembryonic Antigen (CEA) and human epidermal growth factor receptor 2 (HER2). CEA is associated with colon, lung and some breast cancers, while HER2 is a breast cancer marker in approximately 25% of patients. These antigens are found in normal colon lumen and heart muscle respectively. A protein used in finding a molecular target may be something as simple as a mouse‐derived antibody or an engineered protein construct. One constraint is that proteins from alien species eventually generate their own human antibodies when repeatedly used in a given patient. This effect can be moderated by DNA manipulation of the alien antibody to change its structure to a more human‐like amino‐acid sequence. Use of a blood‐injection for the RP may result in sequestration by a normal tissue such as the liver or kidneys. In the renal case, small proteins (<25 kDa) would be very rapidly taken out of circulation so as to prevent significant tumor targeting. Various strategies have been developed to minimize sequestration; e.g., blocking or use of polyethylene glycol covering molecules (“stealth”) to prolong protein circulation. Because of the large numbers of possible RPs, it is necessary that preselection be done on any putative clinical RP. A figure of merit (FOM) may be used to choose one of a series of agents dedicated to the same tumor type; e.g., cognate antibodies to CEA. Both imaging and therapeutic FOMs have been developed. These indicators are used to differentiate RPs using animal data. This preferential ordering process is needed since the number of agents is large while volunteers for research studies are only a small fraction (2 to 5%) of the total patient population. One is still left with the question of the relationship between animal and clinical biodistribution data.Learning Objectives:1. Know the types of agents presently being studied for TRT.2. Understand the reasons for tumor targeting by engineered pharmaceuticals (RPs).3. Realize the importance of the RP blood curve for the targeting process.4. Use of Figures of Merit to select an optimal imaging or therapy agent.

The fundamental equality used in internal emitter absorbed dose (D) estimation is D = S*Ã. Here, D and à are vectors and S is a rectangular matrix. Generally D and à have components assigned to the various body organs. Voxel‐based calculations are also possible if data are obtained in a 3‐D format. The first step in making the estimate is to perform activity (A) measurements in each of the organs that can be visualized in the scanning and/or imaging process. Essentially 6 methods are available for this quantification ranging from inverse‐square counting to quantitative SPECT (QSPECT) or PET. The most common technique is the geometric‐mean method (GM) which requires that two images be acquired simultaneously on each side of the patient. Given a set of counts for each source organ over time A(t), one must integrate numerically to find Ã. It is standard procedure to represent data at times beyond the last imaging point as a physical decay using the half life of the radiolabel. We should note that some agents used for Targeted Radionuclide Therapy (TRT) may not give off photons so that a surrogate agent is used; e.g., 111‐In‐antibody in lieu of 90Y‐antibody.Given the à vector, the estimator then may use S in two types of computations. A type I computation involves using the S matrix obtained from a relevant humanoid phantom. In this case, all organ sizes are specified for a standard man, woman or child and the biological data (Ã) from each animal or patient must be normalized accordingly. Type I calculations are used in regulatory applications and in comparing one agent with another scientifically. Type II computations are patient‐specific in that à is unchanged, but S must be modified to represent the geometry of the individual. In TRT, Type II estimates are made with relatively small amounts of activity prior to the start of therapy. Generally, human S values are standard tabulations available in OLINDA and other software. If murine dose estimates are needed, however, some S values are available. The result of the matrix multiplication of S and à is a set of doses for each of up to 30 or more target tissues. Because of external beam precedents, it is now becoming common to use both D and D2 in the analysis of tumor regression and normal organ toxicity. In this analysis, one plots the clinical outcome, such as tumor size, vs. a quadratic polynomial in dose. One anticipates a sigmodal response. Using such analyses, it is possible that TRT can evolve into a clinical strategy beyond its present limitation to B‐cell lymphomas.Learning Objectives:1. Knowing methods to determine organ activity.2. Realizing the errors in activity measurement.3. Understanding the types of dose estimate (phantom vs patient).4. Using dose as a first step in estimation effectiveness of therapy.

1757 Objectives: Development of SPECT-CT and incorporation of various corrections into image reconstruction and analysis methods have made it possible to achieve accurate activity concentration measurements with SPECT. To optimize our use of SPECT to measure the biodistribution of In-111 labeled monoclonal antibodies (MAbs), we compared activity quantitation from images of an anthropomorphic phantom obtained with two available types of medium-energy collimators. Methods: A human torso phantom was configured with simulated lungs, liver, left kidney and tumors (5, internal diameter 1.0 to 3.3 cm) and filled with known In-111 concentrations approximating the biodistribution of radiolabel 48 h after injection of 185 MBq of an In-111 anti-CEA MAb. Relative activity concentrations were as follows: liver 1, lungs 0.08, kidney 0.3, tumors 0.5, background 0.03. SPECT-CT scans (dual 20%-wide energy windows) were obtained with each set of collimators [measured system FWHM at 0 cm = 4.4 (Set 1) or 5.4 (Set 2) mm; nominal septal penetration 0.14% (Set 1) or 1.2% (Set 2)] using a GE HawkeyeTM tomograph (120 views, 30 s/view). True-count sensitivities for In-111 as determined by Monte Carlo simulation were 88 and 126 cps/kBq for Sets 1 and 2, respectively. Images were reconstructed using the OS-EM algorithm (30 iterations, 24 subsets) including corrections for attenuation, scatter and collimator-detector response. A separately-obtained high-resolution (2.5 mm slice thickness) CT scan was coregistered with the SPECT image sets and used to define regions of interest and measure object volumes for SPECT quantitation. Results: Overall, errors in SPECT-derived activity concentration measurements were smaller for collimator Set 1 than Set 2. {% Error [100(SPECT/true-1)] Set1/Set 2: liver -3.6%/8.6%; lungs 2.7%/12%; kidney -7.7%/-3.6%; 1.0 cm tumor (axilla) -5.9%/-20%; 1.5 cm tumor (abdomen near liver) 21%/36%; 2.1 cm tumor (left lung) -7.8%/2.7%; 3.3 cm tumor (abdomen) -7.1%/8.0%; 3.2 cm tumor (liver) 36%/45%}. Conclusions: Collimator-detector response compensation notwithstanding, benefits to SPECT quantitation from the 40% higher sensitivity of collimator Set 2 were more than offset by its 20% worse spatial resolution and higher septal penetration compared with collimator Set 1.

Inverse correlations of tumor uptake (u), measured in percent injected dose per gram, with tumor mass (m) are demonstrated for phospholipid vesicle, nonspecific and specific monoclonal antibody tracers. Correlation coefficients implied u = B mA in 11 different animal experiments. Experimental exponent (A) values lay in the range -0.28-0.64 with a mean of -0.43 while intercept (B) values varied from 3 to 18. Spherical and cylindrical tumor models implied exponents of -0.33 and -0.5, respectively. Comparison of three implantation sites of the human LS174T xenograft revealed a narrow range of exponents (-0.38- -0.46) indicating a consistent geometry for this tumor. Blood flow to the lesion site and inside its volume (as dictated by tumor size) are factors in tumor uptake. Our results indicate that biodistribution data should include the variation of tumor uptake with mass. For less than 10 g lesions, we predict that radiation absorbed dose will be highly dependent upon tumor size.

A computer system in clinical nuclear medicine has a wide variety of operations which it can perform. These range from simple data acquisition and tabulation to elaborate temporal and spatial reconstructions. Simultaneous recording of physiological data has also expanded the number of nuclear medical studies possible. The multiple-gated cardiac equilibrium analysis is the primary example of this format which has evolved rapidly with the availability of inexpensive central memory. Decreasing size and cost of processor units recently have led to the development of multiple processor systems. In some cases, the peripheral devices have a microprocessor already built in. The total cost of the computer system is essentially dictated by the number of peripheral devices.

In Anger camera imaging, probably the most important parameter of camera performance is field uniformity. For the majority of camera users, field uniformity is evaluated in a subjective manner by simply viewing polaroid field floods. Due to film lim-itations, viewing conditions and statistical limitations, it is questionable if count density differences less than 15-20% can really be identified. To shift from a qualitative to quantitative method of field uniformity determination, a photographic method using high count density 70mm images has been developed. For the majority of Nuclear Medical imaging procedures, the current instrument of choice is the Anger camera. Of the An camera performance parameters, probably the most important is field uniformity. For those few institutions with dedicated computers interfaced to an Anger camera, field uniformity can be assessed and even corrected by the computer. However, for the majority of camera users, no quantitative method of uniformity evaluation exists. To shift from a qualitative to quantitative method of field uniformity determination without an interfaced dedicated computer, a phogographic method using high count density 70mm images has been developed; similar to film isodore methods in radiation therapy.