(This is intended to be a description of my personal involvement in the field, rather than a comprehensive history of the topic.)

The application of PET scanning to the study of receptors was one of the very most exciting and rewarding periods of my career. It started sometime in the 1978. I was an Associate Professor at Johns Hopkins in the Dept of Pharmacology, and I was part of the Neuropharmacology group lead by Sol Snyder. Sol had been identifying drug and neurotransmitter receptors by binding techniques for the past several years. I had been focusing on labeling receptors in vivo followed by autoradiography; in other words, I and others had identified general conditions where, after injection of a radiolabeled ligand, most of the radioactivity in the brain was associated with receptors. Therefore, measurements of the radioactivity provided a measure of receptors since they were preferentially labeled by the radioactive drug.

One day, and I don’t remember exactly when it was, sometime in 1978 I think, Sol received some visitors who told him about PET scanning and how it might be applied to imaging receptors. The basic approach would be the one I was working with, labeling receptors in vivo after intravenous injection of radiolabeled drug or ligand. I enthusiastically got involved, and I got to know some of the key people in the PET world. I went to Brookhaven on May 5, 1978, and observed a PET imaging procedure using a glucose derivative; the experiment was run by Drs Marty Reivich, Al Wolf and Joanna Fowler. It was fascinating to see how a radiolabeled derivative of glucose could be prepared and handled very quickly – quickly was necessary since the positron-emitting isotope had a short half life. PET used external detectors placed around the head that measured the emissions, and subsequent processing of the data allowed the construction of an image of the distribution of radioactivity in the head without invading the head at all. Well, the idea became a big topic of discussion, and Henry Wagner at Hopkins also expressed his interest. He was a radiologist and knew imaging inside and out. We decided to try for a grant. The Brookhaven group asked me to work with them, but Henry Wagner appealed to my loyalty, and I agreed to work only with the Hopkins team.

A first step for our Hopkins group to get into the PET scanning business was to obtain a cyclotron. The cyclotron was needed to synthesize the positron-emitting atoms that could then be incorporated into drugs useful for studies of brain. Wagner’s plan was to write an NIH grant for a state of the art cyclotron.

The grant was titled the “Study of Neuroreceptor Binding in Man” and Wagner was the PI. I was designated the Leader of Project 1, the “Tomographic Localization of Dopamine Receptors in the Brains of Primates and Man”. The goals were to validate the approach for labeling receptors in vivo with non-human primates, and then to proceed to similar studies with humans. The proposal states that “the identification of conditions which allow selective receptor binding of radiolabeled drugs in vivo after intravenous administration….” have been achieved and three papers from my lab were cited (Atweh and Kuhar, 1977, Brain Res 124;53-68; Kuhar and Yamamura, 1975, Nature 253:560-561; Kuhar et al , 1978, Life Sci, 22:203-210.). The grant (NS 15080) was reviewed at a June 10th study section, received a 188 score and at some point a site visit to Hopkins was planned. The planned start date of the grant was 7/1/79 if funded. In a letter dated April 10, 1979 to Henry Wagner, I outlined some priorities that I thought I would be responsible for, and hoped for a “perfect” site visit. His reply on April 12 was in complete agreement.

My role in the project had to do: with the labeling receptors in vivo after intravenous administration, with sharing that knowledge on how to do it and what was required, and how you know it when you have done it. If preferential labeling of receptors could be done, with the ligands prepared with the cyclotron and the chemists, and if the PET machine could measure the radioactivity, then receptor imaging should be possible. As I mention above, part of my job was explaining this to the group so that it became group knowledge. Also, adequate labeling of receptors required higher specific activity radioligands. This was because receptors are relatively low in numbers, and if there is to be an adequate signal to measure, the average radioactivity per molecule had to be relatively high. At one group meeting, Wagner asked me if I could guarantee that PET imaging of receptors would work. I replied that if the chemists could produce ligands of at least 100 Cu per mmole (which in the world of positron chemistry is easy), then we would be able to preferentially label receptors. That I could guarantee. Whether the PET instrument could detect it, I wasn’t sure, but it seemed likely when we looked at the specifications of the machines. Moreover, a French group did publish a paper in the 70s on the PET scanning of cholinergic receptors in vivo in the heart; but we just weren’t sure how it would work or if that was repeatable.

On 8/1/79 the cyclotron grant was funded and the cyclotron was purchased! For my project, we did show that after intravenous injection, a radiolabeled opiate drug preferentially bound to opiate receptors in monkeys (Wamsley et al., Neurosci, 7:595-613, 1982). This was not done by PET imaging but by dissecting the brain after administering the radioactive drug and measuring the radioactivity in brain regions by scintillation counter, and further showing that the distribution of radioactivity after in vivo injection was parallel to that of the distribution of receptors previously demonstrated by accepted procedures. We were rapidly approaching the time when studies in humans could begin.

The five year competing renewal grant application was submitted to the NIH and we were sited visited on Sept 19, 1983. Again Wagner was the PI, I was co-director of the Biology core with James Frost, Jon Links was head of the Physics core, Burns and Dannals and others were in the Chemistry core, Dean Wong was part of a couple of the cores, and there were clinical cores as well. In the end we were approved for 3 more years of funding.

In 1983, we published the first report of dopamine receptor imaging in human brain in Science (vol 221: 1264). Henry Wagner was the human subject! A handwritten note by me in my notebook is as follows: “Yesterday (5/25/83) the first human PET scan of receptors (in brain) rolled off the NeuroEcat. Wagner on the table, Dean Wong injecting, Jon Links at controls and everyone around! That is now done!” Well, I wasn’t exactly correct. It had just begun. On 6/17/83 there was a PET meeting in DC. I gave a good lecture and Wagner was excited, and expressed his desire to be first author on the paper. There was a lot of publicity about the PET work in 1983 and later. There were two very nice articles in the Baltimore Sun (The evening Sun, July 27, 1984; and Evening Sun, Sept 20, 1983) showing Henry Wagner and me standing before the PET scanner and a monitor with a PET image on it (see below).

This was like a fairly tale come true. We were now able to look at the sites of action of drugs (i.e., the receptors) in a living human brain by a non invasive (except for the injection of tracer) procedure. This opened up the study of receptors in living humans, the study of how therapeutic drugs occupied receptors in the brain, and how receptors were affected by neuropsychiatric disease. These studies go on today.

It is a nice story of teamwork, synergy and emergence. I didn’t invent receptor binding, and Wagner didn’t invent cyclotrons or PET, but we all came to the table with our experience and with what we knew and trusted. We pooled it and it worked. I look back and think of key people, of Don Burns, Bob Dannals, Jim Frost, Jon Links, Ursulla Scheffel, Dean Wong and others. Many of these people continued to make outstanding contributions to the PET literature. There were many individual acts of creativity that worked together and helped us reach our goal.

It was am amazing time. One of my proudest achievements is that I was able to have acquired an expertise in an approach and technology that would be a necessary feature of PET scanning of receptors, that is, the labeling receptors in vivo with radioligands. Henry Wagner brought us all together and persisted even though the outcome was uncertain. Many human emotions boiled through us all over those years, and we and Henry wonderfully persisted, and in the end, we were successful. In the next several years, the Hopkins PET Center became one of the most productive and prolific centers of its type anywhere. (11/20/07).

I recently found a letter from Henry Wagner dated June 29, 1994. It was a reply to my letter to Henry (dated may 24, 1994) where I said "Looking back over the years, working with you has been great. You are one of Hopkins' best and it has been a privilege." Henry's reply to me said "Your help to me has been far greater than the reverse. I hope we can continue to work together for many years." It is nice to be appreciated. (Sept 28, 2011).