Tumor hypoxia is an important prognostic indicator for cancer therapy outcome. EF5 [2-(2-nitro-1[ H]-imidazol-1-yl)- N-(2,2,3,3,3-pentafluoropropyl)-acetamide] has been employed to measure tumor hypoxia in animals and humans using immunohistochemical methods. EF5 is a lipophilic molecule designed to have a very uniform biodistribution, a feature of obvious benefit for use in PET imaging. The present study represents the first demonstration of noninvasive PET imaging of rat tumors using fluorine-18 labeled EF5. Because of the small tumor size, partial volume effects may result in underestimation of concentration of the compound. Therefore, validation of the PET data was performed by gamma counting of the imaged tissue. The tumor models studied were the Morris 7777 (Q7) hepatoma (n=5) and the 9L glioma (n=2) grown subcutaneously in rats. Our previous studies have demonstrated that early passage 9L tumors are not severely hypoxic and that Q7 tumors are characterized by heterogeneous regions of tumor hypoxia (i.e., Q7 tumors are usually more hypoxic than early passage 9L tumors). The seven rats were imaged in the HEAD Penn-PET scanner at various time points after administration of 50-100 micro Ci (18)F-EF5 in 30 mg/kg carrier nonradioactive EF5. The carrier was used to ensure drug biodistribution comparable to prior studies using immunohistochemical methods. (18)F-EF5 was excreted primarily via the urinary system. Images obtained 10 min following drug administration demonstrated that the EF5 distributed evenly to all organ systems, including brain. Later images showed increased uptake in most Q7 tumors compared with muscle. Liver uptake remained relatively constant over the same time periods. Tumor to muscle ratios ranged from 0.82 to 1.73 (based on PET images at 120 min post injection) and 1.47 to 2.95 (based on gamma counts at approximately 180 min post injection). Tumors were easily visible by 60 min post injection when the final tumor to muscle ratios (based on gamma counts) were greater than 2. Neither of the 9L tumors nor the smallest Q7 tumor met this criterion, and these tumors were not seen on the PET images. These preliminary results suggest that (18)F-EF5 is a promising agent for noninvasive assessment of tumor hypoxia. Plans are underway to initiate a research project to determine the safety and preliminary evidence for the efficacy of this preparation in patients with brain tumors.

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Highlights 32 33 • Tbx20 plays a role in the development of non-image-forming pathways. 34 35 • Loss of Tbx20-expressing RGCs alters specific aspects of the pupil reflex arc. 36 37 • Previously unknown role for a specific subset of Tbx20-expressing RGCs in 38 modulating pupil size. 39 40 eTOC 41 Dhande et al. identify a novel genetic program that marks and is required for the 42 development of non-image-forming parallel visual pathways. Moreover, chemogenetic 43 activation of a specific retina-to-OPN pathway reveals a novel circuit element controlling 44 pupil size. These findings provide new insight into the mechanisms that establish defining 45 features of functionally specialized sensory pathways. 46 47space. We discovered that Tbx20 expression is mostly restricted to three RGC-types: M1 56 intrinsically photosensitive RGCs (ipRGCs), M2 ipRGCs and 'diving' RGCs. The axonal 57 projections of Tbx20-RGCs innervate non-image-forming brain centers including the 58 suprachiasmatic nucleus, the medial division of the posterior pretectal nucleus, and the 59 olivary pretectal nucleus (OPN), a principal station in the neural pathway for generating 60 the pupillary light reflex (PLR). Conditional deletion of Tbx20 resulted in reduced Tbx20-61 RGC axonal innervation of these targets and revealed a key role of these neurons in driving 62 specific phases of the PLR. Furthermore, chemogenetic activation uncovered a novel role 63 for a specific subset of Tbx20-RGCs in controlling pupil dilation. These data offer a new 64 understanding of the genetic and molecular mechanisms that establish specific, 65 behaviorally-relevant visual circuits. 66 67

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